The role of Toll-like receptors in rheumatoid arthritis

Huang, Qinglan; Pope, Richard M.

doi:10.1007/s11926-009-0051-z

Cited by 213 publications

(169 citation statements)

References 51 publications

(73 reference statements)

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“…TLRs and IL-1R belong to the same IL-1R/TLR superfamily and are believed to play important roles in bacteria-mediated bone loss in diseases including periodontitis, rheumatoid arthritis, and osteomyelitis (14,18,42,(51)(52)(53)(54). Studies have shown that TLR ligands inhibit RANKL-induced osteoclast differentiation from un-committed osteoclast precursors (11,37,38,55), whereas IL-1 potentiates RANKL-induced osteoclast formation (21,56,57).…”

Section: Discussionmentioning

confidence: 99%

IL-1R/TLR2 through MyD88 Divergently Modulates Osteoclastogenesis through Regulation of Nuclear Factor of Activated T Cells c1 (NFATc1) and B Lymphocyte-induced Maturation Protein-1 (Blimp1)

Chen

Su²,

Xu³

et al. 2015

Journal of Biological Chemistry

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Background: Interleukin-1 and Porphyromonas gingivalis both signal through the IL-1R/TLR superfamily but have distinct effects on osteoclastogenesis. Results: IL-1 and P. gingivalis lipopolysaccharide (LPS-PG) differentially regulate osteoclast genes and osteoclastogenic transcription factor NFATc1, as well as transcription repressor Blimp1 and anti-osteoclastogenic genes. Conclusion: Multiple signaling molecules are involved in distinct IL-1R/TLR2-mediated effects on osteoclastogenesis. Significance: This is a novel mechanism for understanding infection/inflammation-mediated osteoclastogenesis.

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Section: Discussionmentioning

confidence: 99%

IL-1R/TLR2 through MyD88 Divergently Modulates Osteoclastogenesis through Regulation of Nuclear Factor of Activated T Cells c1 (NFATc1) and B Lymphocyte-induced Maturation Protein-1 (Blimp1)

Chen

Su²,

Xu³

et al. 2015

Journal of Biological Chemistry

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“…Endogenous ligands for TLR-2 and TLR-4 are found in RA joints. These include gp96, fibrinogen, Hsp60, Hsp70, hyaluronic acid, myeloid-related protein 8/14, and high mobility group box chromosomal protein 1 (26). Indeed, TLR inhibition by a dominant-negative form of the Toll/IL-1R domain containing adaptor protein molecules suppressed the spontaneous production of proinflammatory cytokines and MMPs from RSF (27).…”

Section: Inhibitory Effect Of Endogenous P16 Ink4a On Il-6 Productionmentioning

confidence: 99%

p16INK4a Exerts an Anti-Inflammatory Effect through Accelerated IRAK1 Degradation in Macrophages

Murakami

Mizoguchi

Saito

et al. 2012

The Journal of Immunology

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Induction of cyclin-dependent kinase (CDK) inhibitor gene p16INK4a into the synovial tissues suppresses rheumatoid arthritis in animal models. In vitro studies have shown that the cell-cycle inhibitor p16INK4a also exerts anti-inflammatory effects on rheumatoid synovial fibroblasts (RSF) in CDK activity-dependent and -independent manners. The present study was conducted to discern how p16INK4a modulates macrophages, which are the major source of inflammatory cytokines in inflamed synovial tissues. We found that p16INK4a suppresses LPS-induced production of IL-6 but not of TNF-α from macrophages. This inhibition did not depend on CDK4/6 activity and was not observed in RSF. p16INK4a gene transfer accelerated LPS-triggered IL-1R–associated kinase 1 (IRAK1) degradation in macrophages but not in RSF. The degradation inhibited the AP-1 pathway without affecting the NF-κB pathway. Treatment with a proteosome inhibitor prevented the acceleration of IRAK1 degradation and downregulation of the AP-1 pathway. THP-1 macrophages with forced IRAK1 expression were resistant to the p16INK4a-induced IL-6 suppression. Senescent macrophages with physiological expression of p16INK4a upregulated IL-6 production when p16INK4a was targeted by specific small interfering RNA. These findings indicate that p16INK4a promotes ubiquitin-dependent IRAK1 degradation, impairs AP-1 activation, and suppresses IL-6 production. Thus, p16INK4a senescence gene upregulation inhibits inflammatory cytokine production in macrophages in a different way than in RSF.

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“…Identification of the mechanism whereby these cytokines are induced will not only help to understand the pathogenesis of these diseases but also provide a potential target for drug development. The association of aberrant Tolllike receptor (TLR) responses with these diseases (Lai and Gallo, 2008;Miller, 2008;Huang and Pope, 2009;Carrasco et al, 2011) and the fact that activation of certain TLRs induces TNF-a, IL-1b, and IL-6 production allow speculation that TLR signaling may play a role in disease initiation and/or progression.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Toll-Like Receptor-Mediated Inflammation In Vitro and In Vivo by a Novel Benzoxaborole

Chen¹,

Sexton²,

Gertrudes³

et al. 2012

J Pharmacol Exp Ther

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Pro-inflammatory cytokines play a critical role in the development of autoimmune and inflammatory diseases. Targeting the cytokine environment has proven efficient for averting inflammation. In this study, we reported that, a benzoxaborole analog, inhibited TLR2-, TLR3-, TLR4-, and TLR5-mediated TNF-a, IL-1b, and IL-6 release from human PBMCs and isolated monocytes with IC 50 values ranging from 18 to 580 nM, and the inhibition was mediated at the transcriptional level. Topical administration of AN3485 significantly reduced PMA-induced contact dermatitis and oxazolone-induced delayed-type hypersensitivity in mice, indicating its capability of penetrating skin and potential topical application in skin inflammation. Oral administration of AN3485 showed dose-dependent suppression of LPSinduced TNF-a and IL-6 production in mice with an ED 90 of 30 mg/kg. Oral AN3485, 35 mg/kg, twice a day, suppressed collagen-induced arthritis in mice over a 20-day period. The potent anti-inflammatory activity in in vitro and in vivo disease models makes AN3485 an attractive therapeutic lead for a variety of cutaneous and systemic inflammatory diseases.

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The role of Toll-like receptors in rheumatoid arthritis

Cited by 213 publications

References 51 publications

IL-1R/TLR2 through MyD88 Divergently Modulates Osteoclastogenesis through Regulation of Nuclear Factor of Activated T Cells c1 (NFATc1) and B Lymphocyte-induced Maturation Protein-1 (Blimp1)

IL-1R/TLR2 through MyD88 Divergently Modulates Osteoclastogenesis through Regulation of Nuclear Factor of Activated T Cells c1 (NFATc1) and B Lymphocyte-induced Maturation Protein-1 (Blimp1)

p16INK4a Exerts an Anti-Inflammatory Effect through Accelerated IRAK1 Degradation in Macrophages

Inhibition of Toll-Like Receptor-Mediated Inflammation In Vitro and In Vivo by a Novel Benzoxaborole

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