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p38 MAPK Signaling in Oral-related Diseases

¹ Department of Oral Biology, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214-3008, USA; and
² Department of Periodontics and Oral Medicine, University of Michigan, 1011 N. University Avenue, Ann Arbor, MI 48109-1078, USA

Correspondence: ^* corresponding author, klkirk{at}umich.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION p38 SIGNALING IN CHRONIC... p38 SIGNALING IN... p38 SIGNALING IN DESQUAMATIVE... p38 SIGNALING IN MUCOSITIS... p38 SIGNALING IN CHRONIC... MECHANISMS OF CYTOKINE... p38 MAPK IS A... ARE-BINDING PROTEINS (ARE-BPs)... MOLECULAR ACTION OF TTP... CONCLUSION REFERENCES

 
Multiple dental diseases are characterized by chronic inflammation, due to the production of cytokines, chemokines, and prostanoids by immune and non-immune cells. Membrane-bound receptors provide a link between the extracellular environment and the initiation of intracellular signaling events that activate common signaling components, including p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor (NF)-B. Although ERK pathways regulate cell survival and are responsive to extracellular mitogens, p38 MAPK, JNK, and NF-B are involved in environmental stress responses, including inflammatory stimuli. Over the past decade, significant advances have been made relative to our understanding of the fundamental intracellular signaling mechanisms that govern inflammatory cytokine expression. The p38 MAPK pathway has been shown to play a pivotal role in inflammatory cytokine and chemokine gene regulation at both the transcriptional and the post-transcriptional levels. In this review, we present evidence for the significance of p38 MAPK signaling in diverse dental diseases, including chronic pain, desquamative disorders, and periodontal diseases. Additional information is presented on the molecular mechanisms whereby p38 signaling controls post-transcriptional gene expression in inflammatory states.

Key Words: p38 MAPK • oral diseases • interleukins • tristetraprolin • RNA stability • RNA binding proteins

	INTRODUCTION

TOP ABSTRACT INTRODUCTION p38 SIGNALING IN CHRONIC... p38 SIGNALING IN... p38 SIGNALING IN DESQUAMATIVE... p38 SIGNALING IN MUCOSITIS... p38 SIGNALING IN CHRONIC... MECHANISMS OF CYTOKINE... p38 MAPK IS A... ARE-BINDING PROTEINS (ARE-BPs)... MOLECULAR ACTION OF TTP... CONCLUSION REFERENCES

 
The progression of many inflammatory dental diseases is the result of cytokine overproduction. Briefly, inflammatory insults will interact with host cells, resulting in an immune response by initiating signaling cascades that result in the production of proinflammatory cytokines, pain mediators, and, in chronic cases, severe tissue destruction. Upon receptor activation by inflammatory insults, signaling cascades such as ERK, JNK, NF-B, and p38 can be activated. Of these, the more stress-responsive pathways are JNK, NF-B, and p38. Of late, there has been much focus on the p38 MAPK pathway and its ability to regulate cytokine and chemokine production at transcriptional and post-transcriptional levels. Upon phosphorylation of p38 MAPK, downstream intermediates become phosphorylated. This, in turn, activates gene transcription as well as allowing for the stabilization of the AU-rich element (ARE)-containing mRNA through trans-acting RNA-binding proteins. When the inflammatory stimulus is resolved, the pathway is inactivated via dephosphorylation by MAPK phosphatases (MKP). This review will evaluate the role of p38 MAPK signaling in chronic pain, temporomandibular joint disorders (TMJD), desquamative disorders, mucositis, and stomatitis, as well as chronic periodontitis (Fig. 1). Finally, we will discuss p38 MAPK signaling and potential therapeutic targets. [For a thorough review of p38 MAPK signaling, please refer to the companion article by Schindler et al. in this issue.]

View larger version (25K): [in this window] [in a new window]   Figure 1. Schematic representation of dental diseases where p38 MAPK signaling has been shown to play a significant role relative to the pathobiology of the disease.

	p38 SIGNALING IN CHRONIC PAIN

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Prostaglandins function as proinflammatory agents as well as mediators of pain (Vane, 1971; Zeilhofer, 2007). In addition, PGE₂ is produced at sites of tissue injury (Dionne et al., 2001), and administration of prostaglandins produces vasodilation and edema, augmenting pain perception in animals and humans (Dionne et al., 2001). Bradykinin, an initial inflammatory pain mediator, has a wide gamut of cytokine production. In human gingival fibroblasts, bradykinin increases the levels of IL-8 (Hayashi et al., 2000; Brunius et al., 2005). It also elicits the expression of proinflammatory mediators, such as IL-6 and COX-2-induced PGE₂ (Hayashi et al., 2000; Rodriguez et al., 2006). Bradykinin elicits its effects distinctly through two different receptors: B1 and B2. The increased sensitivity to bradykinin is partly due to increased B2 bradykinin receptor expression. In cultured human bronchial smooth-muscle cells, IL-1β stimulates a cascade initiating the phosphorylation of phospholipase A2, which, in turn, induces COX-2 mRNA expression. As a result of this cascade, B2 receptor gene transcription is increased (Schmidlin et al., 2000). A study in rats as well as human embryonic kidney 293 cells revealed that bradykinin also elicits hyperalgesia and cytokine production via the p38 MAPK pathway, through activation of the bradykinin B1 receptor (Ganju et al., 2001).

MAPKs play an important role not just in the production of proinflammatory cytokines, but also in the progression to chronic pain. A study performed by Crown et al.(2006) revealed that rats receiving spinal cord injuries required activation of p38 MAPK, ERK1/2, and cAMP response element binding protein to progress to chronic central neuropathic pain. A similar observation has been made by Zhang et al.(2005), who reported that chronic constriction of the sciatic nerve resulted in chronic neuropathic pain, and that inhibition of p38 MAPK reversed the mechanical allodynia and thermal hyperalgesia. The function of MAPKs was verified in orofacial areas of rats through small-animal studies wherein p38 and ERK inhibitors reduced IL-1β-induced mirror-image allodynia (Yang et al., 2005).

	p38 SIGNALING IN TEMPOROMANDIBULAR JOINT DISORDER

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Temporomandibular joint disorder (TMJD) has multiple possible etiologies. Several contributing factors for TMJD have been noted, including micro-trauma of the TMJ, immune responses within the TMJ, psychosocial factors, and anatomical structures of the TMJ (Zhang et al., 1999). TMJD signs and symptoms include pain, altered function, and joint noises, which may be neurogenic, inflammatory, and/or traumatic in nature. Importantly, the presence of proinflammatory cytokines results in the destruction of the TMJ through cartilaginous and bone degradation in non-autoimmune- and autoimmune-associated TMJD. Cytokines, such as IL-1β, IL-6, IL-8, and TNF-, are increased in the synovial fluid of persons with TMJ disc degeneration (Fu et al., 1995; Kaneyama et al., 2002). Bone degradation has been highly correlated with the binding of the receptor activator of NF-B (RANK) with its ligand (RANKL), while RANK binding to osteoprotegerin results in an antagonistic effect (Bezerra et al., 2005). Decreased levels of osteoprotegerin correlate with the joint destruction in individuals with osteoarthritis (Kaneyama et al., 2003). Correspondingly, the RANKL:osteoprotegerin ratio is high in the synovia of persons with TMJD (Wakita et al., 2006). The presence of pain mediators such as substance P also contributes to bone resorption via the release of RANKL (Kojima et al., 2006). Tissue destruction is associated with aberrant production of nitric oxide through the overexpression of nitric oxide synthase in pathologic TMJ synovial tissues (Takahashi et al., 2003). Nitric oxide functions as a free radical and is capable of inducing proteases and collagenases (Brennan et al., 2003). Its presence has been associated with increased joint effusion and pain (Suenaga et al., 2001). Furthermore, nitric oxide stimulation of apoptosis is involved in the onset and progression of cartilage destruction in antigen-induced arthritis in rabbit TMJ (Habu et al., 2004).

Several studies have reported increased levels of proinflammatory cytokines in the synovial fluid of persons with TMJD. Calcitonin gene-related peptide is induced by TNF- in rat trigeminal ganglion neurons (Bowen et al., 2006). IL-1 is involved in the hyperplasia and transformation of synovial fibroblasts, resulting in pannus formation as well as cartilage and bone erosion in rheumatoid joint destruction (Feige et al., 1989; Dinarello, 2002). Injection of IL-1 into rabbit knee joints over two weeks resulted in acute and chronic symptoms of arthritis (Feige et al., 1989). In a murine model, IL-1 injections induced chronic erosive synovitis, as well as premature pannus formation (Stimpson et al., 1988). Stromelysin and collagenase expression was increased when stimulated with IL-1 and TNF- in primary human synovial cells (MacNaul et al., 1990). Specifically, IL-1β-induced stromelysin has been attributed to cartilage destruction in rabbit articular joints of collagen-induced arthritis (Hasty et al., 1990). In bone degradation, numerous studies have shown IL-6 involvement. IL-6 is a pleotropic cytokine that has been shown to increase osteoclast development (Jilka et al., 1992). This is further supported by a study showing that IL-6-deficient mice are protected from bone loss after estrogen depletion (Jilka et al., 1992; Passeri et al., 1993; Poli et al., 1994). IL-6 antibody therapy used in rheumatic arthritis therapy has been proven to be successful (Nakahara and Nishimoto, 2006).

The presence of cytokines has become an important predictor in therapies and their outcome. TNF- in human synovial fluid has been associated as a biomarker for pain in persons with internal derangement (Shafer et al., 1994). Members of the interleukin-6 family of cytokines function as biochemical markers of osseous changes in temporomandibular joint disorders (Kaneyama et al., 2004). Using an IL-6^–/– null mouse, Alonzi et al.(1998) demonstrated the crucial need for IL-6 to develop collagen-induced arthritis. IL-6 serves as a negative outcome predictor for persons suffering from chronic closed-lock of the TMJ, while IL-10 was identified as a predictor for successful therapy (Hamada et al., 2006).

	p38 SIGNALING IN DESQUAMATIVE DISORDERS

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Desquamative lesions—such as oral lichen planus, vesiculobullous disorders, mucus membrane pemphigoid, and pemphigus vulgaris—may persist in the human buccal mucosa, tongue, and even the gingiva. Although there are many variations of desquamative disorders, this review will focus on oral lichen planus and pemphigoid lesions such as pemphigus vulgaris. Mucous membrane pemphigoid and other forms of pemphigus lesions will not be discussed, since pemphigoid lesions express similar cytokines to various degrees (Moller et al., 1991; Lee et al., 1993; D’Auria et al., 1997; Bhol et al., 2001; Kumari et al., 2001; Letko et al., 2002; Canizares et al., 2006; Heffernan and Bentley, 2006; Cirillo et al., 2007). The etiology of oral lichen planus is still being identified; however, there is sufficient evidence supporting the occurrence of subepithelial tissue destruction of the basement membrane and keratinocytes through cell-mediated immunity involving CD4⁺ and CD8⁺ T-cells (Sugerman et al., 2002; Sun et al., 2002; Khan et al., 2003). Reticulated and erosive forms of the disorder result in soreness and/or pain, hyperortho- and -para-keratosis, the presence of lymphocytes, basal lamina thickening, and basal cell lysis; however, erosive lichen planus presents as an ulceration after detachment of epithelium (Eversole, 1997; Sugerman et al., 2002; Sun et al., 2002; Khan et al., 2003). The lesions are propagated through cytokine interactions between keratinocytes and lymphocytes (Sugerman et al., 2002; Sun et al., 2002; Khan et al., 2003). Specifically, immunohistochemical and ELISA analysis of CD8⁺ T-cells showed increased levels of IFN- and TNF- (Khan et al., 2003). Although CD8⁺ cells did express high levels of IFN-, when the cells were stimulated with TNF- in vitro, IFN- levels dropped, suggesting a complex cytokine interaction in the progression of disease (Khan et al., 2003). Additional evidence indicates that keratinocytes produce secretory cytokines such as IL-1β, TNF-, and GM-CSF, resulting in the migration of peripheral blood mononuclear cells (Yamamoto et al., 2000). Sixty percent of the mast cells found in oral lichen planus lesions were shown to degranulate and release TNF-, RANTES (chemokine-regulated on activation, normal T-cell-expressed and secreted), and histamine (Moller et al., 1991; Zhao et al., 2001). Previous studies have also shown high expression of IL-6 and IL-1 in persons with oral lichen planus (Yamamoto and Osaki, 1995; Sun et al., 2002; Rhodus et al., 2005, 2006). Thus far, a therapeutic approach utilizing corticosteroids has been proven effective in reducing IL-1, TNF-, IL-6, and IL-8 levels in persons with oral lichen planus (Rhodus et al., 2006).

Pemphigus vulgaris is an autoimmune mucocutaneous blistering disease. Lesions arising from pemphigus vulgaris result from autoantibodies interacting with keratinocytes inducing acantholysis (Amagai et al., 1991). Cytokines involved in disease progression include IL-1, IL-2, IL-5 (Takahashi et al., 2007), IL-10, IL-6, and TNF- (D’Auria et al., 1997; Bhol et al., 2000; Feliciani et al., 2000). The disease propagates predominantly via a TH2 humoral response. IL-5 production in pemphigus vulgaris has been associated with active disease, and promotes the TH2 autoantibody response (K Takahashi et al., 2001; H Takahashi et al., 2007). IL-10 promotes the TH2 response by promoting B-cells to produce autoantibodies (Jeannin et al., 1998). A study by Feliciani et al.(2000) demonstrated the importance of IL-1 and TNF- in pemphigus vulgaris disease progression. The group blocked acantholysis of keratinocytes in vitro with the use of antibodies against IL-1 and TNF- (Feliciani et al., 2000). Further, they evaluated passive transfer of pemphigus vulgaris in IL-1-deficient mice as well as TNF--deficient mice, and found decreased susceptibility to disease progression (Feliciani et al., 2000). High levels of IL-6 and TNF- have been detected in the sera of persons with PV and correlated with disease activity (D’Auria et al., 1997). A polymorphism in the TNF- gene in relation to HLA-DRB1*8 and HLA-DRB1*14 has been associated with predisposition to pemphigus vulgaris (Torzecka et al., 2003). Analysis of clinical data from a case study suggests that the TNF- inhibitor, infliximab, was effective in the management of pemphigus vulgaris disease recurrence (Jacobi et al., 2005). The presence of disease in mice with pemphigus vulgaris is prevented when p38 MAPK inhibitors are used (Berkowitz et al., 2006). Current therapies include the use of high-dose corticosteroids along with other immunosuppressive agents, such as intravenous immunoglobulin therapy (Bhol et al., 2001).

	p38 SIGNALING IN MUCOSITIS AND STOMATITIS

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Ulcerative lesions such as chronic ulcerative stomatitis arise from autoimmune reaction against the host. The disease predominantly affects mucosal tissues and manifests symptoms of soreness and pain. Affected persons have high levels of stratified epithelium-specific antinuclear antibodies, as well as chronic ulcerative stomatitis protein antibodies (Jaremko et al., 1990; Lee et al., 1999). Therapeutic approaches to this disease have been mainly associated with anti-inflammatory reagents such as corticosteroids and anti-rheumatics such as chloroquine and hydroxychloroquine (Jaremko et al., 1990; Fox, 1996). Although the mechanism of action for chloroquine is not completely understood, there is sufficient evidence supporting the inhibition of inflammation-induced TNF- and IL-6 (Fox, 1996; van den Borne et al., 1997). Homeopathic remedies such as Jasminum grandiflorum L have been therapeutic through their free-radical scavenging properties (Umamaheswari et al., 2007). Corticosteroids have been very well-studied in their mechanism of anti-inflammatory action. More recently, these anti-inflammatory properties have been attributed to the induction of C dual-specificity phosphatase-1 (DUSP-1), also known as MAP kinase phosphatase (MKP)-1, which has been shown directly to dephosphorylate p38 MAPK and JNK proteins of inflammation (Toh et al., 2004; Zhao et al., 2005; Abraham and Clark, 2006; Abraham et al., 2006). The role of MKP regulation in p38 MAPK signaling is discussed in greater depth below. The effects of corticosteroids have also been observed in the inhibition of MMP-9 (De Paiva et al., 2006). Cases of mucositis due to cancer therapy have been attributed to poor oral hygiene prior to therapy (Duncan and Grant, 2003), TNF-, and IL-8, as well as reactive oxygen species (Osaki et al., 1994; Lima et al., 2005; Stokman et al., 2006). The use of TNF- inhibitors reduced histological and clinical ulcers in hamsters (Lima et al., 2005). The use of inhibitors such as azelastin hydrochloride, which suppresses the respiratory burst of neutrophils and cytokine release, reduced mucositis and may be utilized as prophylactic treatment (Osaki et al., 1994).

	p38 SIGNALING IN CHRONIC PERIODONTITIS

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In periodontal disease, a unique microenvironment located in the subgingiva fosters the growth of anaerobic bacteria and spirochetes that lead to bacterial colonization/invasion, followed by the irritation and inflammation of host tissues. Many bacterial constituents, including bacterial lipopolysaccharide (LPS), interact with a variety of resident immune and non-immune cells, such as periodontal ligament cells, fibroblasts, osteoblasts, osteoclasts, neutrophils, antigen-presenting cells such as dendritic cells, macrophages, and T-cells, as well as B-cells, to elicit an inflammatory response (Choi et al., 2001; Jotwani et al., 2001; Jotwani and Cutler, 2003; Cutler and Jotwani, 2004, 2006; Mahanonda et al., 2006). Extracts from Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) induce IL-8, a potent chemokine, independent of LPS in gingival epithelial cells (Sfakianakis et al., 2001). The secretion of chemokines allows for dendritic cells, neutrophils, macrophages, and lymphocytes to infiltrate tissues and initiate the innate immune response (Garlet et al., 2003, 2006). Inoculation of C57/Bl6 mice with A. actinomycetemcomitans induces alveolar bone loss and leukocyte migration to gingival tissues (Garlet et al., 2006). Porphyromonas gingivalis (P. gingivalis)-induced destruction of alveolar bone has been attributed to the TH1 immune response (Stashenko et al., 2007). Immunization of mouse calvariae with P. gingivalis results in increased inflammation and tissue destruction through an increased inflammatory response from innate and acquired immunity (Leone et al., 2006).

LPS stimulation of the host immune response results in excessive proinflammatory cytokine production, thus initiating and advancing periodontal disease. A. actinomycetemcomitans (strain Y4) LPS can induce IL-6 at mRNA and protein levels in mouse periodontal ligament (mPDL) fibroblasts (Patil et al., 2006). LPS binds to CD-14, a co-receptor that is present on the macrophage cell surface as well as in serum. Interaction with Toll-like Receptor (TLR)-2 or -4 initiates major intracellular pathways, including NFB and MAPKs. The result of signaling pathway activation is the production of proinflammatory cytokines such as IL-1β, TNF-, IL-6, and RANKL, directly or indirectly in multiple cell lines, including osteoblasts, stromal cells, and leukocytes (Nakashima et al., 2000; Jiang et al., 2002; Kikuchi et al., 2003). LPS additionally induces the production of NO, the free radical, and PGE2 through the p38 MAPK pathway in human gingival fibroblasts (Gutierrez-Venegas et al., 2005). In a recent publication, the lipid A component of P. gingivalis has been shown to induce nitric oxide in RAW264.7 murine macrophages (Choi et al., 2007). Nitric oxide, associated with periodontally inflamed tissues, is capable of inducing matrix metalloprotease (MMP), which results in connective tissue destruction (Matejka et al., 1998; Brennan et al., 2003). In the gingival crevicular fluid, clinical studies have detected elevated levels of IL-6, TNF-, and IL-1β in persons afflicted with periodontitis (Geivelis et al., 1993; Hirose et al., 1997). Elevated IL-6 levels are higher in recurrent periodontitis cases, and increased GCF levels correlate with Gram-negative fimbriae (Reinhardt et al., 1993; Hirose et al., 1997; Al-Shammari et al., 2001). In the periodontium, IL-6 can be produced by a variety of cells, including gingival fibroblasts, macrophages, lymphocytes, and osteoblasts (Takeichi et al., 1994, 1996). Importantly, IL-17, a cytokine secreted by T-cells, has been detected in periodontal lesions through immunoblot and ELISA of periodontal explants (Takahashi et al., 2005). The cytokine is capable of inducing osteoclastogenesis via osteoclast differentiation factor (now known as RANKL) expression in primary murine osteoblasts (Kotake et al., 1999). Importantly, blocking IL-17 with antibodies reduced osteoclast formation in cultures treated with synovial fluid from persons with rheumatoid arthritis (Kotake et al., 1999). IL-17 increases IL-6 and IL-8 in human gingival fibroblasts, as well as IL-1 and TNF- in human peripheral blood monocytes (Beklen et al., 2007). A study by Assuma et al.(1998) demonstrated the importance of IL-1 and TNF- in experimental periodontal bone loss. Here, the group injected soluble receptors of IL-1 and TNF- to inhibit bone loss, osteoclast formation, and recruitment of inflammatory cells to bone (Graves et al., 1998).

It is quite clear that proinflammatory mediators are the major culprits in disease progression. Importantly, many of these cytokines are produced through the actions of p38 MAPK. Currently, 4 isoforms of the p38 MAPK exist: , β, , and . The and β isoforms share the greatest similarity, being roughly 70% identical, based on sequence, while the and isoforms are roughly 60% identical to the isoform. Each isoform is associated with a specific aspect of the stress response. For example, the isoform can induce apoptosis, while the β isoform promotes cell survival in cardiac muscle cells (Wang et al., 1998). An important distinction among these isoforms is their ability to be inhibited by SB203580, a classic p38 pharmacological inhibitor used in numerous studies. The inhibitor is effective only on the and β isoforms, whereas the and isoforms cannot be inhibited (Davies et al., 2000; Enslen et al., 2000). The isoform is ubiquitously expressed, while the β isoform is expressed highly in the brain and heart. The gamma () isoform is mostly expressed in muscle cells, while the delta () isoform is expressed in the lung, kidney, gut, and salivary gland epithelium (Wang et al., 1997). Although these isoforms are expressed at higher concentrations in different tissues, there is evidence that they can all be expressed given the appropriate stimulus (Alonso et al., 2000). All p38 isoforms share conserved residues involved in ATP and ion binding. They share significant sequence similarity in their kinase domain and the 24- to 27-amino-acid N terminal to this domain (Hanks and Hunter, 1995; Jiang et al., 1997). These regions are most likely to be involved in substrate specificity and activity levels.

The , β, , and isoforms can all phosphorylate downstream substrates, such as ATF-2, but, unlike the isoform, the isoform cannot phosphorylate MAPKAPK-2 (MK2) (Goedert et al., 1997). These isoforms also vary in their mode of activation. In 293 transfected cells, the isoform is strongly activated by H₂O₂, UV, and osmotic shock, and moderately by anisomycin, IL-1β, and TNF-. The isoform is also strongly activated by H₂O₂, UV, osmotic shock, and anisomycin, while moderately activated by IL-1β and TNF- (Wang et al., 1997; Wang et al., 1998). Through inhibitor studies, it is apparent that p38 is a key player in inflammation.

p38 MAPK activity depends on the phosphorylation of both tyrosine (Y) and threonine (T) residues (Wilsbacher et al., 1999). Immediate upstream activators of p38, mitogen-activated protein kinase kinase (MKK)-3 and MKK-6, preferentially activate p38 MAPK, depending on the types of stimuli. Our group has shown that A. actinomycetemcomitans LPS-induced IL-6 expression in mPDL cells utilizes the MKK3-p38 pathway, while IL-1β and E. coli LPS are capable of utilizing MKK3 and MKK6 (Patil et al., 2006). MKK3 is required for p38 MAPK activation in inflammatory arthritis (Inoue et al., 2006). Additionally, the MKK3-p38 MAPK pathway plays a greater role in the regulation of cytokines and MMP expression in fibroblast synoviocytes obtained from persons with rheumatoid arthritis (Inoue et al., 2005). Our group has also established the importance of MKK6-p38 MAPK as an important regulator for MMP-13 (Rossa et al., 2005).

Regulation of p38 MAPK involves dephosphorylation through phosphatases such as MKP-1 and PP2A. In vivo studies have reported profound results. Sustained activity of MAPKs due to MKP-1 deficiency results in mice that are highly susceptible to endotoxic shock and autoimmunity from increased TNF- and IL-6 overexpression (Chi et al., 2006; Salojin et al., 2006). Non-selective inhibitors, such as dipyridamole, have been shown to stimulate the activity of MKP-1, thus reducing p38 MAPK activity (Chen et al., 2006). Overexpression of MKP-1 reduces LPS-induced IL-6 and TNF- in macrophages (Chen et al., 2002). PP2A has been associated with inactivation of p38 MAPK-induced IL-6 expression in mast cells (Boudreau et al., 2004). Additionally, attenuation of p38 MAPK activity has been observed through inhibitors such as SB203580, SC409, and SD-282. Our group has shown that IL-1β-induced IL-6 production can be abrogated by the p38 MAPK inhibitor, SB203580, in MC3T3-E1 osteoblast-like cells (Patil et al., 2004). Moreover, A. actinomycetemcomitans LPS-induced IL-6 is diminished to background levels in p38 MAPK-deficient mouse embryonic fibroblast cells (Patil et al., 2006). A study utilizing two different p38 MAPK inhibitors, RO4399247 and AVE8677, in the treatment of arthritic mice identified p38 MAPK as a key component in TNF--mediated inflammatory bone destruction in rheumatoid arthritis (Zwerina et al., 2006). Importantly, the inhibition of p38 MAPK by SC-409 prevents inflammatory bone destruction (Mbalaviele et al., 2006). Additionally, in an LPS-induced bone loss model, our group has also demonstrated the importance of p38 MAPK signaling in LPS-induced alveolar bone destruction in rats (Kirkwood et al., 2007). SD282 (an orally active p38 inhibitor) significantly blocked LPS-induced bone loss, as measured from micro-computed tomography analyses with low and high doses of SD-282 (Fig. 2). Analysis of these data, collectively, suggests that p38 inhibitors may have therapeutic value for the inhibition of cytokine-driven inflammatory bone loss in periodontal inflammation. Additional studies are required to validate these data in an infectious disease periodontitis models.

View larger version (43K): [in this window] [in a new window]   Figure 2. A. actinomycetemcomitans LPS induces significant linear bone loss, which is blocked by an orally active p38 inhibitor. (A) Reformatted µCT isoform display from 8-week-old A. actinomycetemcomitans LPS-injected rat maxillae exhibits dramatic palatal and interproximal bone loss. Landmarks used for linear measurements were the cemento-enamel junction (CEJ) to the alveolar bone crest (ABC). (B) Linear bone loss as measured from the CEJ to the ABC (mean ± SEM). Significant bone loss (p < 0.01) was observed between control (n = 6) and A. actinomycetemcomitans LPS-injected rats (n = 12). Significant reduction of LPS-induced periodontal bone loss (**p < 0.01 for SD-282 [15 mg/kg; n = 8] and *p < 0.05 for SD-282 [45 mg/kg; n = 8]). Used with permission (Kirkwood et al., 2007).

	MECHANISMS OF CYTOKINE EXPRESSION MEDIATED THROUGH p38 MAPK SIGNALING

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	p38 MAPK IS A KEY REGULATOR OF mRNA STABILITY

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View larger version (34K): [in this window] [in a new window]   Figure 3. RNA-binding proteins mediate regulation of cytokine mRNA stability through p38/MK2 signaling. LPS activates p38 MAPK signaling in a variety of cells, leading to transcriptional activation of cytokine genes or enhanced mRNA stability and translation (highlighted areas). The fate of ARE mRNA is dependent on the presence of destabilizing and stabilizing mRNA binding proteins. p38 MAPK activates MK2 in the nucleus, allowing for MK2 translocation to the cytoplasm. MK2 subsequently phosphorylates destabilizing mRNA-binding proteins such as TTP. This action prevents TTP from interacting with ARE cytokines. Simultaneously, activation of the p38 MAPK pathway results in translocation of HuR, a stabilizing RNA-binding protein, from the nucleus to the cytoplasm. Thus, upon p38/MK2 activation and phosphorylation of TTP, cytokine mRNA stability is enhanced, because TTP is no longer dictating mRNA triage and exonuclease decay.

	ARE-BINDING PROTEINS (ARE-BPs) DICTATE mRNA TURNOVER

TOP ABSTRACT INTRODUCTION p38 SIGNALING IN CHRONIC... p38 SIGNALING IN... p38 SIGNALING IN DESQUAMATIVE... p38 SIGNALING IN MUCOSITIS... p38 SIGNALING IN CHRONIC... MECHANISMS OF CYTOKINE... p38 MAPK IS A... ARE-BINDING PROTEINS (ARE-BPs)... MOLECULAR ACTION OF TTP... CONCLUSION REFERENCES

However, the role of ARE mRNA degradation is not solely encapsulated by exosome activity. A recent publication by Stoecklin et al.(2006) demonstrated the need for P-bodies as well as exosomes in ARE mRNA degradation. Here, β-globin-ARE mRNA-stable human cells were transfected with siRNA to knock down specific components of either pathway. Key components—such as 5' to 3' exoribonuclease-1, Sm-like proteins 1-7, and the exosomal component polymyositis-scleroderma autoantigen-75—were identified as factors contributing to ARE mRNA degradation. The results demonstrate a need for a 5'–3' pathway for ARE mRNA degradation (Stoecklin et al., 2006).

At least 20 different proteins that can bind to ARE segments have been identified to date. However, only a subset of these ARE-BPs has been shown to influence the stability or translational efficiency of their target mRNAs. An overview of ARE-BPs known to have an mRNA regulatory function is presented in Table 2. T-cell-restricted intracellular antigen-1 and T-cell-restricted intracellular antigen-1-related protein both inhibit translation of certain ARE-containing mRNAs, while Hu protein R stabilizes ARE-mRNAs. In contrast, the AU-rich element RNA-binding protein 1 and KH-type splice regulatory protein are involved in destabilizing ARE-containing mRNAs (see Table 3 and indicated references). TTP and TTP-related proteins, butyrate response factors (BRF)-1 and -2, have a major regulatory role in controlling cytokine mRNAs. The TTP/BRF families of proteins bind to AREs with relatively high specificity through a characteristic zinc finger domain. The function of TTP was elucidated through several studies with TTP-deficient mice (Varnum et al., 1991). TTP^–/– mice were shown to develop a generalized inflammatory condition, including an arthritic-like syndrome, secondary to increased TNF- and GM-CSF levels (Taylor et al., 1996). In TTP^–/–mice, increased cytokine production was shown to be a result of increased mRNA stability (Carballo et al., 1998, 2000). TTP binds to mRNAs to promote rapid degradation (see below). Butyrate response factor-1 was functionally cloned and found to have a function similar to that of TTP (Stoecklin et al., 2002). Butyrate response factor-1 was shown to have the capacity to degrade GFP-reporter-containing AREs of TNF-, GM-CSF, IL-2, IL-3, and IL-6 (Stoecklin et al., 2002). Overexpression studies have confirmed that TTP and butyrate response factors-1 and -2 induce the degradation of mRNAs containing cytokine AREs (Jiang et al., 2002; Stoecklin et al., 2003; Sully et al., 2004). Despite this knowledge of TTP function, no studies to date have evaluated the role of TTP in chronic inflammatory dental diseases.

	MOLECULAR ACTION OF TTP INVOLVES PHOSPHORYLATION AND CYTOPLASMIC LOCATION

TOP ABSTRACT INTRODUCTION p38 SIGNALING IN CHRONIC... p38 SIGNALING IN... p38 SIGNALING IN DESQUAMATIVE... p38 SIGNALING IN MUCOSITIS... p38 SIGNALING IN CHRONIC... MECHANISMS OF CYTOKINE... p38 MAPK IS A... ARE-BINDING PROTEINS (ARE-BPs)... MOLECULAR ACTION OF TTP... CONCLUSION REFERENCES

View larger version (30K): [in this window] [in a new window]   Figure 4. Molecular actions of TTP to ensure that rapid mRNA decay is mediated through p38 MAPK signaling. In the absence of inflammatory stimulation, TTP binds ARE cytokine mRNA and shuttles the message to exosomal and P-body degradation sites, where mRNA is degraded by exonucleases in the 3' to 5' direction or the 5' to 3' direction, respectively. Upon activation of the p38 MAPK-MK2 pathway, TTP is phosphorylated at serines 52 and 178. Phosphorylation at these sites sequesters TTP from ARE mRNA and allows for interaction with 14-3-3 proteins. The ARE mRNAs are now capable of interacting with stabilizing components, which shuttle the transcript to translational machinery (see text for details).

	CONCLUSION

TOP ABSTRACT INTRODUCTION p38 SIGNALING IN CHRONIC... p38 SIGNALING IN... p38 SIGNALING IN DESQUAMATIVE... p38 SIGNALING IN MUCOSITIS... p38 SIGNALING IN CHRONIC... MECHANISMS OF CYTOKINE... p38 MAPK IS A... ARE-BINDING PROTEINS (ARE-BPs)... MOLECULAR ACTION OF TTP... CONCLUSION REFERENCES

	ACKNOWLEDGMENTS

 
Due to space constraints, we were unable to cite every important reference relating to this large field of research.

This work was supported by the National Institutes of Health Grants DE018290 and DE007034 and by Department of Defense grant W81XWH-05-0075.

Received for publication May 3, 2007. Revision received June 27, 2007. Accepted for publication June 29, 2007.

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TOP ABSTRACT INTRODUCTION p38 SIGNALING IN CHRONIC... p38 SIGNALING IN... p38 SIGNALING IN DESQUAMATIVE... p38 SIGNALING IN MUCOSITIS... p38 SIGNALING IN CHRONIC... MECHANISMS OF CYTOKINE... p38 MAPK IS A... ARE-BINDING PROTEINS (ARE-BPs)... MOLECULAR ACTION OF TTP... CONCLUSION REFERENCES

 

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Journal of Dental Research, Vol. 86, No. 9, 812-825 (2007)
DOI: 10.1177/154405910708600903


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