Deleterious effects of cytokine over-production in periodontal diseases

Introduction

The complex human body handles innumerable processes synchronously every day and without error. However, with respect to oral bacterial infection, it is the body's own protective processes that lead to the ultimate destruction of the periodontium. The molecular pathways involved in the various diseases known as periodontitis have puzzled the minds of researchers for decades. In recent years, the involvement of numerous and specific cytokines has helped unveil some control pathways of this disease. Understanding the correct pathway for pharmacological intervention could prove to be a valuable clinical asset for the treatment of periodontitis. The key is to allow the body's natural immune response to continue against the infection, but to seize the corresponding destruction of the periodontium.

This review is intended to serve as a summary of some of the biological mechanisms that contribute to the destructive nature of these diseases. It is intended to piece together some of the various interactions of cells and the signaling molecules that are involved. It is important to realize that the system being described is one that occurs naturally and without disease in many individuals, but encounters some sort of imbalance in the case of the diseased individual. Although key molecules have been known about for years it is not clearly understood whether the diseased state is caused by an uncontrolled regulation of certain harmful substances, or by the loss of inhibition over already present harmful substances. Likewise, it is unknown whether harm is due to an over-sensitivity or increase in number of receptors to harmful substances. This review is not intended to directly answer these questions, but rather, to display the evidence that supports either theory. Further research will eventually conclude the exact pathway, and where it deviates from the norm.

Molecules involved in periodontitis

Interleukin-1

Interleukin-1 (IL-1) was amongst the first cytokines to be complicated with periodontal bone loss. It was first termed in 1979 to describe the multitude of molecules that have been complicated with immune dysfunction but not sought to be the same molecule (^{Aarden et al., 1979}). It is released from macrophages, endothelial cells, keratinocytes, epithelial cells, fibroblasts, T-cells, B-cells amongst the few to be mentioned (^{Dinarello, 1988}). Although a variety of cells have the potential to produce IL-1, ^{Matsuki et al. (1991)} demonstrated that macrophages are predominantly responsible for its production. Its immune function is to stimulate T-cell proliferation, B-cell proliferation and differentiation, and induce fever (^{Slots and Taubman, 1992}). Some of its other functions include, but are not limited to, macrophage activation, natural killer cell stimulation, prostaglandin formation, and cytokine gene expression (^{Tatakis, 1993}). In the periodontally diseased environment, through some of its above mentioned functions, it is linked with major bone resorption (^{Dinarello, 1996}).

IL-1 is a highly inflammatory cytokine that can affect virtually all cell types of the human body. Its genetic family includes three members : IL-1α, IL-1ß, and IL-1 receptor antagonist (IL-1Ra). IL-1Ra is a naturally secreted antagonist unique to cytokine biology (^{Dinarello, 1996}). Both IL-1α and IL-1ß exhibit similar biologic activity, but IL-1ß is about 13-fold more potent (^{Wood et al., 1985}). More so, the internal gene expression of IL-1ß occurs for a longer duration (over 24 hours) when stimulated by IL-1 itself than by any other non-bacterial agent (^{Schindler et al., 1990}). This suggests an amplification loop of IL-1ß production. As one possible repression mechanism, IL-1Ra may potentially limit the response to higher concentrations of IL-1. Although IL-1Ra is genetically related to the IL-1 agonists, it is differentially regulated, and particularly activated by the presence of immunoglobulin-gamma (IgG) and granulocyte-macrophage colony-stimulating factor (GM-CSF). It has been demonstrated that peripheral blood mononuclear cells increased IL-1Ra production up to 18-fold in response to IgG (^{Poutsiaka et al., 1991}). Such an activation pattern, if present in active tissue macrophages, may serve as a signal to the proinflammatory cells that specific immunity has been triggered, and there is no longer a need for antigen (Ag) presentation, T-cell activation, and/or non-specific phagocytosis of Ag. However, this activation would take effect towards the end of the specific immune process to local infection, and as such, would not stop any prior harmful effects of IL-1 or other cytokines. In comparison with IL-1ß production, it has been shown that IL-1Ra production begins 1-2 hours later in lipopolysaccharide (LPS) stimulated human blood monocytes (^{Arend, 1993}). Once bound, IL-1Ra is an effective inhibitor of signal transduction, as a 10⁷-fold molar excess of IL-1Ra over IL-1ß is required for signal transduction in healthy humans (^{Granowitz et al., 1992}). However, a single amino acid substitution can convert the effective IL-1Ra antagonist into a potent agonist (^{Ju et al., 1991}). To induce inhibition of IL-1, a 10- to 100-fold IL-1Ra quantity is required (^{Arend et al., 1990}). This is due to the significantly lower rate of association of IL-1Ra with the type I receptor, despite the near equal affinities of IL-1 and IL-1Ra for the type I receptor (^{Dinarello, 1996}). This suggests that although IL-1Ra is a necessary repressor of IL-1 activity, by itself it is probably insufficient under normal production. Irikura et al. demonstrated that IL-1Ra's function in the immune response is to regulate the peak leukocyte levels, the accumulation of leukocytes at sites of infection, and the activation of macrophages during a primary infection. As well, IL-1Ra plays a lesser role during a secondary infection (^{Irikura et al., 1999}). These studies suggest a much more complex role of IL-1Ra than previously believed. However, since the effects of IL-1Ra seem to be dependent on IL-1 quantity, an over expression of IL-1 may be too potent to be regulated by this system. Likewise, an over expression of IL-1Ra may be a method of regulating an over expression of IL-1. It was observed that in HIV patients with opportunistic meningoencephalitis the cerebrospinal fluid contained an imbalance between IL-1 and IL-1Ra (IL-1Ra being markedly elevated) (^{Rimaniol et al., 1997}). Clinical investigations involving the administration of a recombinant form of IL-1Ra to patients suffering from rheumatoid arthritis proved to be preliminarily beneficial, though the dose and frequency were important for the efficacy of the treatment (^{Champion et al., 1996}). Clearly, IL-1Ra warrants further investigation.

There are two IL-1 receptors : IL-1RI and IL-1RII. IL-1RI is the receptor that actually transduces the chemical signal, while IL-1RII is a « decoy » receptor, and may serve as a neutralizer or damper of IL-1 signaling (^{Garrett et al., 1993} ; ^{Colotta et al., 1994}). Both receptors are members of the Ig superfamily, each composed of three highly homologous IgG-like domains (^{Sims et al., 1988} ; ^{McMahan et al., 1991}). IL-1 itself is believed to be a prime regulator of IL-1RI expression. Several studies have shown that IL-1 down-regulates its own receptor, both gene and surface expression (^{Ye et al., 1992} ; ^{Pronost et al., 1993} ; ^{Takii et al., 1994}). Yet, if prostaglandin E2 (PGE2) synthesis is concurrent with IL-1 stimulation, IL-1 up-regulates the transcription of its own receptor (^{Takii et al., 1992}). Also, IL-2 and IL-4 have been shown to up-regulate expression of the IL-1RI receptor, both its gene transcription and surface expression (^{Ye et al., 1992} ; ^{Koch et al., 1992}). A very important finding is that cells expressing the IL-1RI need less than ten receptors to transduce a biological response, unlike other hormonal factors that require a much larger receptor pool for effective signaling (^{Dinarello, 1991}). This finding suggests a very high sensitivity to IL-1, alluding to the low picomolar concentrations of IL-1 effective in signal transduction.

Clearly, any changes in surface expression of IL-1RI impact the response to IL-1, however, changes in IL-1RI mRNA intracellularly do not necessarily involve surface changes. Therefore, findings of increased IL-1RI DNA transcription do not necessarily imply increased surface expression, as there may be other intracellular factors that prevent the protein's externalization.

The IL-1RII receptor is molecularly similar to the IL-1RI receptor in its extracellular portion, but it lacks a signal transducing cytosolic domain (^{Bristulf et al., 1994}). Another interesting feature of the IL-1RII is that its extracellular portion can be found soluble in body fluids, in which state it is termed IL-1sRII. In this state, the receptor can bind free IL-1 molecules, perhaps acting as a buffer. Conversely, it is also possible that the removal of IL-1 from body fluids by IL-1sRII may trigger further secretion of IL-1 as its fluid concentration drops. This matter needs to be further investigated in the future.

IL-1 is a very potent osteoclast-stimulating factor, both in vivo and in vitro, and both directly and indirectly (^{Gowen et al., 1983} ; ^{Sabatini et al., 1988} ; ^{Thomson et al., 1986} ; ^{Yu and Ferrier, 1993}). The inflammatory process leading to periodontitis is believed to involve Gram negative bacteria LPS, such as that of Porphyromonas gingivalis, leading to the stimulation of local macrophages. In turn, activated macrophages release cytokines such as IL-1 and TNF (see below) (^{Wilson et al., 1996}). Further, the strength of the inflammatory response to LPS has been shown do be strain dependent (^{Shapira et al., 1998}). The secreted IL-1, among other effects, stimulates T-helper cells, leading to the secretion of IL-2 (^{Vander et al., 1998}). IL-2 is an autocrine agent, that promotes maturation and differentiation of T-helper cells, and it activates macrophages (^{Vander et al., 1998}). This positive feedback mechanism assures a strong and perpetuated immune response to the foreign invading bacteria.

More recently, researchers have been attempting to determine whether periodontitis has a genetic factor. The inflammatory response to infection is a normal occurrence in healthy individuals, but in periodontal diseases it is mal-controlled. ^{Kornman and di Giovine (1998)} correlated one polymorphism within the IL-1 gene with a 2- to 4-fold increase in IL-1ß production. However, this genetic association could only be assessed when smokers were excluded from the analysis. Thus, this study concluded that genetics alone may play a role in the development of periodontitis, but the combination with smoking is also a definite risk factor. In a similar study, ^{McDevitt et al. (2000)} demonstrated the same correlation. They show that two or more polymorphisms in the IL-1 gene constitute a 3,75 to 5,27 increased odds ratio of developing periodontitis in non-smokers or former light-smokers. However, they also show that smokers alone have an increased odds ratio of 7,43 over non-smokers of developing periodontitis. Therefore, both IL-1 genotyping and smoking are risk factors for periodontal disease.

IL-1 is amongst the most investigated cytokines believed to be involved in periodontitis. Much research has implicated its involvement in the inflammatory response as well as in bone resorption, both directly and indirectly. In the cascade of cytokine secretions, the relatively upstream IL-1 production may not be the most ideal region for pharmacological intervention as IL-1 is also essential for immune protection. Ultimately, a worthy pharmacological agent would be capable of inhibiting IL-1's effects of bone cells alone, while allowing other cell interactions to proceed as normal.

Tumor necrosis factor

Tumor necrosis factor (TNF) is a pleiotropic molecule and a member of the TNF ligand superfamily. TNF (previously TNF-α) and its structural homologue lymphotoxin-α (LT-α, previously called TNF-ß) both have similar functions and can bind to the same receptors (^{Sedgwick et al., 2000}). TNF is mainly a product of cells of the monocyte/macrophage lineage, whereas LT-α a mainly a product of B-and T-cells. TNF is also reported to be a product of glial cells, Kupffer cells, keratinocytes, mastocytes, B-and T-cells (^{Szatmary, 1999}). It has also been found in human breast milk (^{Rudloff et al., 1992}).

TNF demonstrates a broad spectrum of biological activities. As its name implies, TNF was first identified for its anticancer effects. TNF plays an undoubtedly important role in the immune response, yet, its effects can be both beneficial and damaging to the host. Depending on stimulated receptor pathway, TNF can lead to either cell survival or apoptosis (^{Goeddel, 1999}). In osteoblasts it has been linked with the inhibition of DNA and collagen synthesis, while stimulating synthesis of plasminogen activators, matrix metalloproteinases (MMP), as well as monoctyte/macrophage colony-stimulating factor (M-CSF), IL-8, and IL-6 (^{Chaudhary et al., 1992} ; ^{Nanes et al., 1989} ; ^{Panagakos and Kumar, 1994} ; ^{Ishimi et al., 1990} ; ^{Felix et al., 1989}). Stimulation of osteoblasts by TNF has been directly associated with the subsequent activation of osteoclasts, with the consequence of bone resorption (^{Thomson et al., 1987}). It has been reported that TNF activates mature osteoclasts and stimulates proliferation and differentiation of pre-osteoclasts (^{Kitazawa et al., 1994} ; ^{Lerner and Ohlin, 1993} ; ^{Van der Pluijm et al., 1991}). A more detailed study by ^{Azuma et al. (2000)} showed that TNF, via the p55r, directly induces the differentiation of osteoclasts from osteoclast progenitors in the presence of M-CSF. ^{Abu-Amer et al. (1997)} show that of all the major osteoclastogenic cytokines only TNF mediates the commitment of bone marrow macrophages (BMM) to the osteoclast phenotype under the induction of LPS. As well, various studies have shown that the effects of TNF and IL-1 on osteoclasts are autocrine, indicating that both these cytokines can perpetuate their own signals in osteoclasts (^{O'Keefe et al., 1997} ; ^{Tani-Ishii et al., 1999}). Through, but not limited to, these actions it is believed that TNF promotes bone resorption, leading to the periodontally diseased state. TNF is considered a potent osteoclastogenic agent.

TNF exerts its effects via two receptors : TNF-R1 (p55r) and TNF-R2 (p75r), each signaling by means of a distinct intracellular pathway (^{Goeddel, 1999}). Recent findings have shown opposing roles of the two receptors. Specifically, p55r enhances the recruitment of osteoclasts and the number of committed osteoclast precursor cells whereas p75r decrease the magnitude and rate of basal and TNF-stimulated osteoclastogenesis (^{Abu-Amer et al., 2000}). The extracellular domains of p75r can be shed and found as soluble ligand (^{Bjornberg et al., 1994}). This suggests a possible buffering effect of TNF by soluble p75r, and may be the method by which this receptor decreases the osteoclastogenic effects of TNF. ^{Abu-Amer et al. (2000)} further showed that soluble TNF is the principal ligand for p55r signaling promoting osteoclastogenesis, and a membrane-bound form of TNF is the main ligand for p75r signaling promoting survival and events such as T-cell activation and GM-CSF production. Selective targeting of soluble or membrane-bound TNF and/or p55r or p75r may hold insight into clinical methods of periodontal treatment.

Much research has focused on the TNF gene transcription regulators. It was hypothesized that the transcription factor NF-κB was implicated in this process (^{Iotsova et al., 1997}). A NF-κB binding site is found in the promoter region of the TNF gene, and NF-κB is translocated into the nucleus of LPS-stimulated monocytes (^{Nedwin et al., 1985} ; ^{Muller et al., 1993}). However, later studies observed controversial involvement of NF-κB in TNF gene expression, and alluded to the existence of another DNA-binding protein (^{Takashiba et al., 1995}). Further investigation led to the finding of a novel transcription factor named LPS-induced TNF-alpha factor (LITAF) that binds the TNF promoter region, suggesting it partakes a key role in TNF gene regulation (^{Myokai et al., 1999}).

TNF has proven to be a bearer of many effects, but among these, it has been shown to mediate bone resorption. The recent findings of its dual and opposite receptor pathways might hold some clues as to a method of exogenously regulating its system. The stabilization of both TNF and IL-1 levels may be a method to control periodontal bone loss in patients with periodontitis.

Interleukin-6

Interleukin-6 (IL-6) is a pleiotropic multifunctional cytokine regulating many cell functions. IL-6 is produced by immune cells, cells of the monocyte/macrophage lineage, fibroblasts, osteoblasts, stromal cells, and keratinocytes to mention a few (^{Ishimi et al., 1990} ; ^{Heinrich et al., 1990} ; ^{Yang et al., 1988}). More specifically, ^{Sanders et al. (1998)} postulated that it is the osteoblast that offers a site at which enhancement of IL-6 production can be achieved, and later followed by increased bone resorption. IL-6 is believed to mediate the effects of IL-1 and/or TNF by stimulating osteoclast formation and osteoclastogenic bone resorption (^{Devlin et al., 1998}). ^{Devlin et al. (1998)} also show that although IL-6 may be a part of the normal body's bone resorption processes of calcium homeostasis, it is not essential for those pathways. Therefore, IL-6 may have a more unique role in the mediation of inflammatory-related bone resorption. ^{De Cesaris et al. (1998)} show that TNF alone is capable of inducing IL-6 production. Subsequently, ^{Neale et al. (1999)} demonstrated the direct synergetic influence of IL-6 and M-CSF in the differentiation of osteoclasts, and the little influence that TNF has on this process.

In the inflammatory process, IL-6 is intended to stimulate B-cell differentiation and maturation, and T-cell differentiation and proliferation (^{Slots and Taubman, 1992}). It is a key activator of the immune response. IL-6 stimulates IgG production from activated B-cells, and an IL-6 deficiency can lead to a reduced antimicrobial resistance, impaired T-cell growth and function, impaired B-cell maturation, and deficient mucosal IgA production (^{Papanicolaou et al., 1998}). However, over-expression of IL-6 in bone has been highly correlated with severe bone loss due to osteoclast cell formation (^{Kotake et al., 1996}). Although IL-6 may increase the recruitment of osteoclasts, some researchers believe that it does not enhanced osteoclast function, as it does not enhance pit-forming activity of osteoclasts (^{Suda et al., 1997}). Nevertheless the increased number of osteoclast at an unchanged activity level would logically still lead to an increased resorption rate.

Signaling of IL-6 is achieved in a rather unique manner. The IL-6 receptor (IL-6R) is a single-pass transmembrane receptor incapable of transducing a biological signal (^{Papanicolaou et al., 1998}). Instead, after the formation of the IL-6-IL-6R complex, the IL-6R dimerizes with a transmembrane glycoprotein known as gp130, which initiates a trasnduction cascade (^{Kishimoto et al., 1995}). Ward et al. also show the possibility of the formation of a high affinity hexameric complex consisting of two molecules each of IL-6, soluble IL-6R, and soluble gp130 (^{Ward et al., 1994}). Signals mediated via gp130 are involved in the immune response, as the gp130 subunit not only functions for IL-6 but for numerous other IL-6 related cytokines of the immune milieu (^{Matsuda et al., 1995}). Further findings suggest that it is the Ig-like gp130 module, specifically, that is required for effective IL-6 signaling (^{Hammacher et al., 1998}). The IL-6R also has a second soluble form (sIL-6R) that consists of its extracellular membrane domains, and is still capable of transducing signals via activation of gp130, even on cells that lack the IL-6R (^{Papanicolaou et al., 1998}). IL-6 has been reported to stimulate formation of osteoclast-like cells only in the presence of sIL-6R (^{Tamura et al., 1993}). As well, IL-6 and sIL-6R have been reported to cause a significant induction of collagenase-3 in rat osteoblasts, a type of collagen degrading MMP (^{Franchimont et al., 1997}).

IL-6 is a product of IL-1 and TNF stimulation in the diseased state, but it is also a normally produced cytokine of bone homeostasis and immune processes. As such, any therapy aimed to eradicate its natural concentration might potentially result in an immune-compromised situation. Again, the ability to localize its receptors only on bone cells, and not on immune cells, might prove to be beneficial.

Interleukin-11

Interleukin-11 (IL-11) is a pleiotropic IL-6-type cytokine, with only a limited homology to IL-6 (^{Paul et al., 1990}). Various stromal cells including, but not limited to, fibroblasts, epithelial cells and osteoblasts produce IL-11 (^{Leng and Elias, 1997b}). It is the conflicting effects of IL-11 on different cells that have puzzled researchers for some time. Induction of IL-11 secretion varies from tissue to tissue, but includes transforming growth factor-ß (TGF-ß), IL-1, TNF, parathyroid hormone (PTH), calcium, and others (^{Elias et al., 1994} ; ^{Martuscelli et al., 2000}). According to ^{Girasole et al. (1994)}, IL-11 promotes osteoclast development and inhibits bone formation. As well, IL-11 was reported to inhibit macrophage production of TNF, IL-1ß, nitric oxide and IL-12 by an expression of the inhibitor of NF-kB (IkB) nuclear factor (^{Trepicchio et al., 1996} ; ^{Leng and Elias, 1997a} ; ^{Trepicchio et al., 1997}). IL-11 has also been complicated with macrophage proliferation and differentiation, stimulation of B-cell Ig production, production of tissue inhibitor of metaloproteinases-1 (TIMP-1), and survival of epithelial cells (^{Leng and Elias, 1997b} ; ^{Du and Williams, 1994} ; ^{Orazi et al., 1996}). Clinical trials of recombinant human IL-11 on Beagle dogs with periodontal disease revealed promising results in terms of IL-11's ability to decrease attachment loss and maintain higher bone densities (^{Martuscelli et al., 2000}). The signaling method of IL-11 bares similarity with that of IL-6. IL-11 signaling is mediated via an IL-11 receptor (IL-11R) and a signal transducing gp130 subunit (used in other IL-6-type cytokine receptors) (^{Romas et al., 1996}). Further knowledge of the IL-11 signaling pathways is yet to be attained.

A further understanding of IL-11's effects, and the ability to determine the specific pathways that lead to bone destruction or the arrest of osteoclastogenesis are essential at this time. If targeted properly, IL-11 has the potential to become a site of pharmacological intevention.

Monocyte/macrophage colony-stimulating factor

Monocyte/macrophage colony-stimulating factor (M-CSF) is a cytokine involved in osteoclast survival (^{Jimi et al., 1995}). The ability of M-CSF to directly influence osteoclasts is evident by the abundant number of M-CSF receptors found on osteoclasts (^{Hofstetter et al., 1992}). Other osteoclastogenic promoting functions of M-CSF have already been mentioned.

Other molecules of periodontitis

IL-12 stimulates the differentiation of naive T cells to the T-helper-1 (Th1) lineage, resulting in interferon-g (INF-g) production, which can lead to further tissue destruction (^{Trepicchio et al., 1999}). INF-γ has also been reported to inhibit IL-11 production, hence decreasing its beneficial activities (^{Trepicchio et al., 1997}). As well, INF-γ has been shown to enhance macrophage production of both IL-1 and TNF, perpetuating further bone resorption (^{Donnelly et al., 1990}). To the contrary, some researchers have reported that INF-γ inhibits IL-1-induced osteoclast formation and bone resorption (^{Takahashi et al., 1986} ; ^{Gowen et al., 1986}).

INF-γ also induces the production of inducible nitric oxide synthase enzyme, responsible for nitric oxide (NO) production, associated with inflammatory tissue injury (^{Nussler and Billiar, 1993}). The effect of NO on osteoclastogenesis is also a controversial issue. ^{Van `T Hof and Ralston (1997)} demonstrated that cytokine-induced osteoblast NO production leads to apoptosis of osteoclast progenitors and decreases the resorptive effects of mature osteoclasts. The specific cytokines that were found to have dramatic 50- to 70-fold enhancement of NO production were INF-γ, IL-1, and TNF. On the other hand, Chapple demonstrated that macrophage-produced NO can react with oxygen radicals, and through a multitude of chemical reactions, can lead to prostaglandin formation, which plays a key role in lymphokine production and osteoclastogenesis (^{Chapple, 1997}). Chapple also mentioned that the induction of NF-kB by reactive oxygen species might be a method of inflammatory cytokine regulation.

IL-4 and IL-10, both produced by the differentiated T-helper-2 (Th2) lineage, demonstrate a role in the inflammatory and bone resorption. IL-4 has been shown to inhibit macrophage synthesis of IL-1ß, TNF, and IL-6 (^{Te Velde et al., 1990}). IL-10 has been shown to suppress macrophage production of INF-γ, as well as other pro-inflammatory cytokines (^{Iwasaki et al., 1998}). Hart et al. demonstrated that IL-4 down regulated and IL-10 up-regulated the TNF p75r on monocytes, and that IL-4 was capable of decreasing IL-10 (^{Hart et al., 1996}). This finding suggests the possibility that IL-4 and IL-10 act opposingly on TNF signaling, and their balance may be important for normal function.

MMP are sought to be part of the terminal effector enzymes having a significant role on bone matrix breakdown (^{Birkedal-Hansen, 1993}). Recent studies have demonstrated a correlation between specific activated MMP-2 in gingival tissue and adult periodontitis (^{Korostoff et al., 2000}). MMP transcription is induced by IL-1 and TNF, and in most cases repressed by INF-γ (^{Birkedal-Hansen et al., 1993}). MMP production can be induced in virtually any cell provided the right signals are present (^{Birkedal-Hansen, 1993}). Regulation of MMP may prove to be a promising therapy to minimize tissue destruction, yet allowing all the upstream immune processes to proceed.

Prostaglandins, produced mainly by osteoblasts, are important signals for bone formation and resorption (^{Suda et al., 1992} ; ^{Raisz et al., 1979} ; ^{Sato et al., 1986}). Prostaglandin E2 induces osteoclast formation and stimulates osteoclastogenesis (^{Akatsu et al., 1991} ; ^{Tai et al., 1997}). ^{Miyaura et al. (2000)} recently demonstrated with prostaglandin receptor EP4-knockout mice that PGE2 is important in bone destruction, and particularly in induction of MMP-2 and MMP-13. PGE2 has also been shown to induce MMP transcription in macrophages (^{Wahl and Wahl, 1985}).

IL-8, produced by Th2 cells, stromal cells, osteoblasts, and osteoclasts serves as a chemotactic factor for more immune cell migration into the local area of inflammation (^{Rifas, 1998}). Further, IL-8 secretion can be induced in stromal and osteoblast-like cells by IL-1 and TNF, and in endothelial cells by IL-1 alone (^{Chaudhary and Avioli, 1994} ; ^{Kaplanski et al., 1994}). Clearly, an over-accumulation of immune cells, and their further production of inflammatory cytokines may play a role in the progression of periodontitis.

Transforming growth factor-ß1 (TGF-ß1) acts upon osteoblasts and other osteoblastic stromal cell lines causing the production of osteoclastogenesis inhibitory factor (OCIF), leading to arrest of osteoclast formation and enhanced apoptosis of osteoclasts (^{Murakami et al., 1998}). TGF-ß has also been shown to repress the production of MMPs (^{Woessner, 1991}).

Although IL-1, TNF, and IL-6 have been a focus of periodontal research for some time now, it is clear that numerous other chemical messengers play a role in periodontal diseases. Perhaps the localization on the more downstream molecules such as the MMP's for example may have fewer negative effects on the immune system. However, it is always important to remember that all the molecules mentioned above are naturally occurring substances in the healthy state, and it is an imbalance of the system that results in deleterious effects on the periodontium.

Synergism

The above-mentioned molecules, their activators and actions map out complex network of regulation of osteoclastogenesis. However, another very important factor remains ; two or more molecules may act in concert to produce a response far greater than the quantitative sum of the separate responses.

^{Stashenko et al. (1987)} demonstrated a 2-fold increase in IL-1 and 100-fold increase in TNF due to their synergism. The effects of IL-1 and TNF are evident by the observation that antagonists to both cytokines significantly decreased the inflammatory response and bone loss in a model of periodontitis in primates (^{Assuma et al., 1998}). Although the importance of IL-1 and TNF in the potentiation cannot be disclaimed, some research suggests that IL-1 and TNF account only partially for LPS-induced bone resorption (^{Chiang et al., 1999}). One study that used TNF and IL-1 receptor knockout mice concluded that IL-1 and TNF are not required for bacteria-induced bone resorption, but are essential to protect against a mixed anaerobic infection (^{Chen et al., 1999}). To the researchers'surprise, the mice lacking both IL-1 and TNF receptors exhibited the greatest amount of osteoclastogenesis. Although these findings remain largely contradictory to an overwhelming abundance of contrary proof, they should not be ignored. Clearly there are other mechanisms that control osteoclastogenesis, and research to be done to discover them.

Summary

To summarize the various interactions of factors and cells in periodontal disease, the ^{figures 1}, ², ³, ⁴, ⁵, ⁶, ⁷ and ⁸ are intended to illustrate the intricate network described in this paper.

Acknowledgements

This work was supported by a grant NIDCR R01 12482.

BIBLIOGRAPHIE

• Aarden LA, Brunner TK, Cerottini JC. Revised nomenclature for antigen-nonspecific T-cell proliferation and helper factors. J Immunol 1979;123:2928-2929.
• Abu-Amer Y, Erdmann J, Kollias G, Alxopoulou L, Ros FP, Teitelbaum SL. Tumor necrosis factor receptors type 1 and 2 differentially regulate osteoclastogenesis. J Biol Chem 2000;275:27307-27310.
• Abu-Amer Y, Ross FP, Edwards J, Teitelbaum SL. Lipopolysaccharide-stimulated osteoclastogenesis is mediated by tumor necrosis factor via its P55 receptor. J Clin Invest 1997;100:1557-1565.
• Akatsu T, Takahashi N, Udagawa N, Imamura K, Yamaguchi A, Sato K et al. Role of prostaglandins in interleukin-1-induced bone resorption in mice in vitro. J Bone Miner Res 1991;6:183-190.
• Arend WP. Interleukin-1 receptor antagonist. Adv Immunol 1993;54:167-227.
• Arend WP, Welgus HG, Thompson RC, Eisenberg SP. Biological properties of recombinant human monocyte-derived interleukin-1 receptor antagonist. J Clin Invest 1990;85:1694-1697.
• Assuma R, Oates T, Cochran D, Amar S, Graves D. IL-1 and TNF antagonists inhibit the inflammatory response and bone loss in experimental periodontitis. J Immunol 1998;160:403-409.
• Azuma Y, Kaji K, Katogi R, Takeshita S, Kudo A. Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts. J Biol Chem 2000;275:4858-4864.
• Birkedal-Hansen H. Role of cytokines and inflammatory mediators in tissue destruction. J Periodont Res 1993;28:500-510.
• Birkedal-Hansen H, Moore WG, Budden MK, Windsor LJ, Birkedal-Hansen B, DeCarlo A et al. Matrix metalloproteinases: a review. Crit Rev Oral Biol Med 1993;4:197-250.
• Bjornberg F, Lantz M, Olsson I, Gullberg U. Mechanisms involved in the processing of the p55 and the p75 tumor necrosis factor (TNF) receptors to soluble receptor forms. Lymph Cyt Res 1994;13:203-211.
• Bristulf J, Gatti S, Malinowsky D, Bjork L, Sundgren AK, Bartfai T. Interleukin-1 stimulates the expression of type I and type II interleukin-1 receptors in the rat insulinoma cell line Rinm5F ; sequencing a rat type II interleukin-1 receptor cDNA. Eur Cyt Network 1994;5:319-330.
• Champion GV, Lebsack ME, Lookabaugh J, Gordon G, Catalano M. Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. The IL-1Ra Arthritis Study Group. Arthritis Rheum 1996;39:1092-1101.
• Chapple ILC. Reactive oxygen and antioxidant in inflammatory diseases. J Clin Periodontol 1997;24287-296.
• Chaudhary LR, Avioli LV. Dexamethasone regulates IL-1beta and TNF-alpha-induced interleukin-8 production in human bone marrow stromal and osteoblast-like cells. Calcif Tissue Int 1994;55:16-20.
• Chaudhary LR, Spelsberg TC, Riggs BL. Production of various cytokines by normal human osteoblast-like cells in response to interleukin-1beta and tumor necrosis factor-alpha : lack of regulation by 17 beta-estradiol. Endocrinology 1992;130:2528-2534.
• Chen CP, Hertzberg M, Jiang Y, Graves DT. Interleukin-1 and tumor necrosis factor receptor signaling is not required for bacteria-induced osteoclastogenesis and bone loss but is essential for protecting the host from a mixed anaerobic infection. Am J Pathol 1999;155:2145-2152.
• Chiang CY, Kyritsis G, Graves DT, Amar S. Interleukin-1 and tumor necrosis factor activities partially account for calvarian bone resorption induced by local injection of lipopolysaccharide. Infect Immun 1999;67:4231-4236.
• Colotta F, Dower SK, Sims JE, Mantovani A. The type II « decoy » receptor : a novel regulatory pathway for interleukin-1. Immunol Today 1994;15:562-566.
• De Cesaris P, Starace D, Riccioli A, Padula F, Filippini A, Ziparo E. Tumor necrosis factor-alpha induces interleukin-6 production and integrin ligand expression by distinct transduction pathays. J Biol Chem 1998;13:7566-7571.
• Devlin RD, Reddy SV, Savino R, Ciliberto G, Roodman GD. IL-6 mediates the effects of IL-1 or TNF, but not PTHr P or 1,25(OH)2D3, on osteoclast-like cell formation in normal human bone marrow cultures. J Bone Miner Res 1998;13:393-399.
• Dinarello CA. Biology of interleukin 1. The Federation of American Societies for Experimental Biology 1988;2:108-115.
• Dinarello CA. Interleukin-1 and interleukin-1 antagonism. Blood 1991;77:1627-1652.
• Dinarello CA. Biologic basis of interleukin-1 in disease. Blood 1996;87:2095-2147.
• Donnelly RP, Fenton MJ, Finbloom DS, Gerrard TL. Differential regulation of IL-1 production in human monocytes by INF-gamma and IL-4. J Immunol 1990;145:569-575.
• Du XX, Williams DA. IL-11 : a multifunctional growth factor derived from the hematopoietic microenvironment. Blood 1994;83:2023-2030.
• Elias JA, Sheng T, Einarsson O, Landry M, Trow T, Rebert N et al. Epithelial interleukin-11 : regulation by cytokines, respiratory syncytial virus, and retnoic acid. J Biol Chem 1994;269:22261-22268.
• Felix R, Fleisch H, Elford PR. Bone resorbing cytokines enhance release of macrophage colony-stimulating activity by the osteoblastic cell MC3T3-E1. Calcif Tissue Int 1989;44:356-360.
• Franchimont N, Rydziel S, Delany AM, Canalis E. Interleukin-6 and its soluble receptor cause a marked induction of collagenase expression in rat osteoblat cultures. J Biol Chem 1997;272:12144-12150.
• Garrett IR, Guise TA, Bonewalk LF, Chizzonite R, Mundy GR. Evidence that interleukin-1 mediates its effects on bone resorption via the 80 kilodalton interleukin-1 receptor. Calcif Tissue Int 1993;52:438-441.
• Girasole G, Passeri G, Jilka RL, Manolagas SC. Interleukin-11 : a new cytokine critical for osteoclast development. J Clin Invest 1994;93:1516-1524.
• Goeddel DV. Signal transduction by tumor necrosis factor. Chest 1999;116(suppl.):69s-73s.
• Gowen M, Nedwin GE, Mundy GR. Preferential inhibition of cytokine-stimulated bone resorption by recombinant interferon gamma. J Bone Miner Res 1986;1:469-474.
• Gowen M, Wood DD, Ihrie EJ, McGuire MKB, Russell RGG. An interleukin-1 like factor stimulates bone resorption in vitro. Nature 1983;306:378-380.
• Granowitz EV, Porat R, Mier JW, Pribble JP, Stiles DM, Bloedow DC et al. Pharmacokinetics, safety, and immunomodulatory effects of human recombinant interleukin-1 receptor antagonist in healthy humans. Cytokine 1992;4:353-360.
• Hammacher A, Richardson RT, Layton JE, Smith DK, Angus LJL, Hilton DJ et al. The immunoglobulin-like module of gp130 is required for signaling by inteleukin-6, but not by leukemia inhibitory factor. J Biol Chem 1998;273:22701-22707.
• Hart PH, Hunt EK, Bonder CS, Watson CJ, Finlay-Jones JJ. Regulation of surface and soluble TNF receptor expression on human monocytes and synovial fluid macrophages by IL-4 and IL-10. J Immunol 1996;157:3672-3680.
• Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochemistry J 1990;265:621-636.
• Hofstetter W, Wetterwald A, Cecchini MC, Felix R, Fleisch H, Mueller C. Detection of transcripts for the receptor for macrophage colony-stimulating factor, c-fms, in murine osteoclasts. Proc Natl Acad Sci USA 1992;89:9637-9641.
• Iotsova V, Caamano J, Loy J, Yang Y, Lewin A, Bravo R. Osteopetrosis in mice lacking NF-kappa1 and NF-kappa2. Nature Med 1997;3:1285-1289.
• Irikura VM, Hirsch E, Hirsh D. Effects of interleukin-1 receptor antagonist overexpression on infection by Listeria monocitogenes. Infect Immun 1999;67:1901-1909.
• Ishimi Y, Miyaura C, Jin CH, Akatsu T, Abe E, Nakamura Y et al. IL-6 is produced by osteoblasts and induces bone resorption. J Immunol 1990;145:3297-3303.
• Iwasaki Y, Hara Y, Koji T, Shibata Y, Nakane PK, Kato I. Differential expression of INF-gamma, IL-4, IL-10, and IL-1beta mRNAs in decalcified tissue sections of mouse lipopolysaccharide-induced periodontitis mandibles assessed by in situ hybridization. Histochem Cell Biol 1998;109:339-347.
• Jimi E, Shuto T, Koga T. Macrophage colony-stimulating factor and interleukin-1alpha maintain the survival of osteoclast-like cells. Endocrinology 1995;136:808-811.
• Ju G, Labriola-Tompkins E, Campen CA, Benjamin WR, Karas J, Plocinski J et al. Conversion of the inteleukin 1 receptor antagonist into an agonist by site specific mutagenesis. Proc Natl Acad Sci USA 1991;88:2658-2662.
• Kaplanski G, Farnarier C, Kaplanski S, Porat R, Shapiro L, Bongrand P et al. Interleukin-1 induces interleukin-8 secretion from endothelial cells by a juxtacrine mechanism. Blood 1994;84:4242-4248.
• Kishimoto T, Akira S, Narazaki M, Taga T. Interleukin-6 family of cytokines and gp130. Blood 1995;86:1243-1254.
• Kitazawa R, Kimble RB, Vannice JL, Kung VT, Pacifici R. Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice. J Clin Invest 1994;94:2397-2406.
• Koch KC, Ye K Clark BD, Dinarello CA. Interleukin 4 (IL-4) up-regulates gene and surface IL-1 receptor type 1 in murine T-helper type 2 cells. Eur J Immunol 1992;22:153-157.
• Kornman KS, oi Giovine FS. Genetic variations in cytokine expression : a risk factor for severity of adult periodontitis. Ann Periodontol. 1998;3:327-338.
• Korostoff JM, Wang JF, Sarment DP, Stewart JCF, Feldman RS, Billings PC. Analysis of in situ protease activity in chronic adult periodontitis patients : expression of activated MMP-2 and a 40 kDa serine protease. J Periodontol 2000;71:353-360.
• Kotake S, Sato K, Kim KJ, Takahashi N, Udagawa N, Nakamura I et al. Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res 1996;11:88-95.
• Leng SX, Elias JA. Interleukin-11 inhibits macrophage interleukin-12 production. J Immunol 1997a ;159:2161-2168.
• Leng SX, Elias JA. Molecules in focus : interleukin-11. Int J Biochem Cell Biol 1997b ;29:1059-1062.
• Lerner UH, Ohlin A. Tumor necrosis factors alpha and beta can stimulate bone resorption in cultured mouse calvariae by a prostaglandin-independent mechanism. J Bone Miner Res 1993;8:147-155.
• Martuscelli G, Fiorellini JP, Crohin CC, Howell TH. The effect of inteleukin-11 on the progression of ligature-induced periodontal disease in the beagle dog. J Periodontol 2000;71:573-578.
• Matsuda T, Fukada T, Takahashi-Tezuka M, Okuyama Y, Fujitani Y, Hanazono Y et al. Activation of Fes tyrosine kinase by gp130, an interleukine-6 family cytokine signal transducer, and their association. J Biol Chem 1995;270:11037-11039.
• Matsuki Y, Yamamoto T, Hara K. Interleukin-1 mRNA-expressing macrophages in human chronically inflammed gingival tissues. Am J Pathol 1991;138:1299-1305.
• McDevitt MJ, Wang HY, Knobelman C, Newman MG, di Giovine FS, Timms J et al. Interleukin-1 genetic association with periodontitis in clinical practice. J Periodontol 2000;71:156-163.
• McMahan CJ, Stack JL, Mosley B, Cosman D, Lupton SD, Brunton LL et al. A novel IL-1 receptor cloned from B-cells by mammalian expression, is expressed in many cell types. Eur Mol Biol Org J 1991;10:2821-2832.
• Miyaura C, Inada M, Suzawa T, Sugimoto Y, Ushikubi F, Ichikawa A et al. Impaired bone resorption to prostaglandin E2 in prostaglandin receptor EP4-knockout mice. J Biol Chem 2000;275:19819-19823.
• Muller JM, Ziegler-Hettbrock HWL, Baeuerle PA. Nuclear factor kappa B, a mediator of lipopolysaccharide effects. Immunobiol 1993;187:233-256.
• Murakami T, Yamamoto M, Yamamoto M, Ono K, Nishikawa M, Nagata N et al. Transforming growth factor-beta1 increase mRNA levels of osteoclastogenesis inhibitory factor in osteoblast/stormal cells and inhibits the survival of murine osteoclast-like cells. Biochem Biophys Res Comm 1998;252:747-752.
• Myokai F, Takashiba S, Lebo R, Amar S. A novel lipopolysaccharide-induced transcription factor regulating tumor necrosis factor alpha gene expression : molecular cloning, sequencing, characterization, and chromosomal assignment. Proc Natl Acad Sci USA 1999;96:4518-4523.
• Nannes MS, McKoy WM, Marx SJ. Inhibitory effects of tumor necrosis factor-alpha and interferon-gamma on deoxyribonucleic acid and collagen synthesis by rat osteosarcoma cells (ROS 17/2.8). Endocrinology 1989;124:339-345.
• Neale SD, Sabokar A, Howie DW, Murray DW, Athanasou NA. Macrophage colony-stimulating factor and interleukin-6 release by periprosthetic cells stimulates osteoclast formation and bone resorption. J Ortop Res 1999;17:686-694.
• Nedwin GE, Nayler SL, Sakaguchi AY, Smith D, Jarrett-Nedwin J, Pennica D et al. Human lymphotoxin and tumor necrosis factor genes : structure, homology and chromosomal localization. Nucleic Acids Res 1985;13:6361-6373.
• Nussler AK, Billiar TR. Inflammation, immunoregulation and inducible nitric oxide synthase. J Leuk Biol 1993;54:171-178.
• O'Keefe RJ, Teot LA, Singh D, Puzas JE, Rosier RN, Hicks DG. Osteoclasts constitutively express regulators of bone resorption : an immunohistochemical and in situ hybridization study. Lab Invest 1997;76:457-465.
• Orazi A, Xunxiang D, Yang Z, Kashai M, Williams DA. Inteleukin-11 prevents apoptosis and accelerates recovery of small intestinal mucosa in mice treated with combines chemotherapy and radiation. Lab Invest 1996;75:33-42.
• Panagakos FS, Kumar S. Modulation of proteases and their inhibitors in immortal human osteoblast-like cells by tumor necrosis factor-alpha in vitro. Inflammation 1994;18:243-265.
• Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med 1998;128:127-137.
• Paul SR, Bennett F, Calvetti JA, Kelleher K, Wood CR, Ohara RM et al. Molecular cloning of a cDNA encoding interleukin-11, a stromal cell-derived lymphopoietic cytokine. Proc Natl Aca Sci USA 1990;87:7512-7516.
• Poutsiaka DD, Clark BD, Vannier E, Dinarello CA. Production of interleukin-1 receptor antagonist and interleukin-1beta by peripheral blood mononuclear cells is differentially regulated. Blood 1991;78:1275-1281.
• Pronost S, Delecouillerie G, Redini F, Paolozzi L, Vivien D, Galera P et al. Interleukin-1 and naproxen down-regulate the expression of IL-1 receptors in cultured human rheumatoid synovial cells. Agents Actions 1993;39:213-217.
• Raisz LG, Vanderhoek JY, Simmons HA, Kream BE, Nicolaou KC. Prostaglandin synthesis by fetal rat bone in vitro : evidence for a role of prostacyclin. Prostaglandins 1979;17:905-914.
• Rifas L. Bone and cytokines : beyond IL-1, IL-6 and TNF-alpha. Calcif Tisue Int 1998;64:1-7.
• Rimaniol AC, Zylberberg H, Rabian C, De Groote D, Zavala F, Viard JP. Imbalance between IL-1 and IL-1 receptor antagonist in the cerebrospinal fluid of HIV-infected patients. J AIDS 1997;16:340-342.
• Romas E, Udagawa N, Zhou H, Tamura T, Saito M, Taga T et al. The role of gp130-mediated signals in osteoclast development : regulation of interleukin-11 production by osteoblasts and distribution of its receptors in bone marrow cultures. J Exp Med 1996;183:2581-2591.
• Rudloff HE, Schmalstieg FC Jr, Muchtaha AA, Palkowetz KH, Liu SK, Goldman AS. Tumor necrosis factor-alpha in human milk. Pediatr Res 1992;31:29-33.
• Sabatini M, Boyce B, Aufdemorte T, Bonewald L, Mundy GR. Infusions of recombinant human interleukin-1alpha and 1beta cause hypercalcemia in normal mice. Proc Natl Acad Sci USA 1988;85:5235-5239.
• Sanders JL, Tarjan G, Foster SA, Stern PH. Alendronate/Interleukin-1beta cotreatment increases interleukin-6 in bone and UMR-106 cells : dose dependence and relationship to the antiresorptive effect of alendronate. J Bone Miner Res 1998;13:786-792.
• Sato K, Fujii Y, Kasono K, Saji M, Tsushima T, Shizum K. Stimulation of prostaglandin E2 and bone resorption by recombinant human interleukin-1alpha fetal mouse bones. Biochem Biophys Res Comm 1986;138:618-624.
• Schindler R, Ghezzi P, Dinarello CA. IL-1 induces IL-1. IV. INF-γ supresses IL-1 but not polyliposaccharide-induced transcription of IL-1. J Immunol 1990;144:2216-2222.
• Sedgwick JD, Riminton DS, Cyster JG, Korner H. Tumor necrosis factor : a master-regulator of leukocyte movement. Immunol Today 2000;21:110-113.
• Shapira L, Champagne C, Van Dyke TE, Amar S. Strain-dependent activation of monocyte and inflammatory macrophages by lipopolysaccharide of Porphyromonas gingivalis. Infect Immun 1998;66:2736-2742.
• Stashenko P, Dewhirst FE, Peros WJ, Kent RL, Ago JM. Synergistic interactions between interleukin 1, tumor necrosis factor, and lymphotoxin in bone resorption. J Immunol 1987;138:1464-1468.
• Sims JE, March CJ, Cosman D, Widmer MB, MacDonald HR, McMahan CJ et al. cDNA expression cloning of the IL-1 receptor, a member of the immunoglobin superfamily. Science 1988;241:585-589.
• Slots J, Taubman MA. Contemporary oral microbiology and immunology. St. Louis : Mosby, 1992.
• Suda T, Nakamura I, Jimi E, Takahashi N. Regulation of osteoclast function. J Bone Miner Res 1997;12:869-879.
• Suda T, Takahashi N, Martin TJ. Modulation of osteoclast differentiation. Endocrine Rev 1992;13:66-80.
• Szatmary Z. Tumor necrosis factor-alpha : molecular-biological aspects minireview. Neoplasma 1999;46:257-266.
• Tai H, Miyaura C, Pilbeam CC, Tamura T, Ohsugi Y, Koishihara Y et al. Transcriptional induction of cyclooxygenase-2 in osteoblasts is involved in interleukin-6-induced osteoclast formation. Endocrinology 1997;138:2372-2379.
• Takahashi N, Mundy GR, Roodman GD. Recombinant human interferon-gamma inhibits formation of human osteoclast-like cells. J Immunol 1986;137:3544-3549.
• Takashiba S, van Dyke TE, Shapira L, Amar S. Lipopolysaccharide-inducible and salicylate-sensitive culear factor(s) on human tumor necrosis factor alpha promoter. Infect Immun 1995;63:1529-1534.
• Takii T, Akahoshi T, Kato K, Hayashi H, Marunouchi T, Onozaki K. Interleukin-1 upregulates transcription of its own receptor in a human fibroblast cell line TIG-1. Role of endogenous PGE2 and cAMP. Eur J Immunol 1992;22:1221-1227.
• Takii T, Hayashi H, Marunouchi T, Onozaki K. Interleukin-1 downregulates type 1 interleukin-1 receptor mRNA expression in a human fibroblast cell line TIG-1 in the absence of prostaglandin E(2) synthesis. Lymph Cyt Res 1994;13:213-219.
• Tamura T, Udagawa N, Takahashi N, Miyaura C, Tanaka S, Yamada Y et al. Soluble interleukin-6 receptor triggers osteoclast formation by interleukin-6. Proc Natl Acad Sci USA 1993;90:11924-11928.
• Tani-Ishii N, Tsunoda A, Teranaka T, Umemoto T. Autocrine regulation of osteoclast formation and bone resorption by IL-1alpha and TNFalpha. J Dent Res 1999;78:1617-1623.
• Tatakis DN. Interleukin-1 and bone metabolism : a review. J Periodontol 1993;64:416-431.
• Te Velde AA, Huijbens RJF, Heije K, de Vries JE, Figdor CG. Interleukin-4 (IL-4) inhibits secretion of IL-1beta, tumor necrosis factor alpha, and IL-6 by human monocytes. Blood 1990;76:1392-1397.
• Thomson BM, Mundy GR, Chambers TJ. Tumor necrosis factors alpha and beta induce osteoblastic cells to stimulate osteoclastic bone resorption. J Immunol 1987;138:775-779.
• Thomson BM, Saklatvala J, Chambers TJ. Osteoblasts mediate interleukin 1 stimulation of bone resorption by rat osteoclasts. J Exp Med 1986;164:104-112.
• Trepicchio WL, Bozza M, Pedneault G, Dorner AJ. Recombinant human IL-11 attenuates the inflammatory response through down regulation of proinflammatory cytokine release and nitric oxide production. J Immunol 1996;157:3627-3634.
• Trepicchio WL, Ozawa M, Walters IB, Kikuchi T, Gilleaudeau P, Bliss J et al. Interleukin-11 therapy selectively downregulates type I cytokine proinflammatory pathways in psoriasis lesions. J Clin Invest 1999;104:1527-1537.
• Trepicchio WL, Wang L, Bozza M, Dorner AJ. IL-11 regulates macrophage effector function through inhibition of nuclear factor-kappaB. J Immunol 1997;159:5661-5670.
• Vander A, Sherman J, Luciano D. Human physiology : the mechanisms of body functin. Boston: WCB/McGraw Hill, 1998.
• Van der Pluijm G, Most W, Van der Wee-Pals L, de Groot H, Papapoulos S, Lowik C. Two distinct effects of recombinant human tumor necrosis factor-alpha on osteoclast development and subsequent resorption of mineralized matrix. Endocrinology 1991;129:1596-1604.
• Van 'T Hof RJ, Ralston SH. Cytokine-induced nitric oxide inhibits bone resorption by inducing apopstosis of osteoclast progenitors and supressing osteoclast activity. J Bone Miner Res 1997;12:1797-1804.
• Wahl SM, Wahl LM. Regulation of macrophage collagenase, prostaglandin, and fibroblast-activating-factor production by anti-inflammatory agents : different regulatory mechanisms for tissue injury and repair. Cell Immunol 1985;92:302-312.
• Ward LD, Howlett GJ, Discolo G, Yasukawa K, Hammacher A, Moritz RL et al. High affinity interleukin-6 receptor is a hexameric complex consisting of two molecules each of interleukin-6, interleukin-6 recetor, and gp-130. J Biol Chem 1994;269:23286-23289.
• Wilson M, Reddi K, Henderson B. Cytokine-inducing components of periodontopathogenic bacteria. J Periodont Res 1996;31:393-407.
• Woessner JF Jr. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. The Federation of American Societies for Experimental Biology 1991;5:2145-2154.
• Wood DD, Bayne EK, Goldring MB, Gowen M, Hamerman D, Humes JL et al. The four biologically distinct species of human interleukin-1 all exhibit similar biological activities. J Immunol 1985;134:895-903.
• Yang YC, Tsai S, Wong GG, Clark SC. Interleukin-1 regulation of hematopoietic growth factor production by human stromal fibroblasts. J Cell Physiol 1988;134:292-296.
• Ye K, Kock KC, Clark BD, Dinarello CA. Interleukin-1 downregulates gene and surface expression of interleukin-1 receptor type 1 by destabilizing its mRNA whereas interleukin-2 increases its expression. Immunology 1992;75:427-434.
• Yu H, Ferrier J. Interleukin-1alpha induces sustained increase in cytosolic free calcium in cultured rabbit osteoclasts. Biochem Biophys Res Commun 1993;191:343-350.