The Role of IL‐1 and IL‐1Ra in Joint Inflammation and Cartilage Degradation

Jacques, Claire; Gosset, Marjolaine; Bérenbaum, Francis; Gabay, Cem

doi:10.1016/s0083-6729(06)74016-x

Cited by 166 publications

(111 citation statements)

References 172 publications

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“…The proinflammatory cytokine TNF plays an important role in the pathogenesis of rheumatoid arthritis (RA) and Crohn's disease, and biological agents that block its activity have been used to treat these diseases [87,88]. However, only a fraction of RA and Crohn's sufferers respond well to anti-TNF antibodies.…”

Section: Tpl-2 Kinase As An Anti-inflammatory Drug Targetmentioning

confidence: 99%

Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase

Gantke¹,

Sriskantharajah²,

Ley³

2010

Cell Res

130

157

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The IκB kinase (IKK) complex plays a well-documented role in innate and adaptive immunity. This function has been widely attributed to its role as the central activator of the NF-κB family of transcription factors. However, another important consequence of IKK activation is the regulation of TPL-2, a MEK kinase that is required for activation of ERK-1/2 MAP kinases in myeloid cells following Toll-like receptor and TNF receptor stimulation. In unstimulated cells, TPL-2 is stoichiometrically complexed with the NF-κB inhibitory protein NF-κB1 p105, which blocks TPL-2 access to its substrate MEK, and the ubiquitin-binding protein ABIN-2 (A20-binding inhibitor of NF-κB 2), both of which are required to maintain TPL-2 protein stability. Following agonist stimulation, the IKK complex phosphorylates p105, triggering its K48-linked ubiquitination and degradation by the proteasome. This releases TPL-2 from p105-mediated inhibition, facilitating activation of MEK, in addition to modulating NF-κB activation by liberating associated Rel subunits for translocation into the nucleus. IKK-induced proteolysis of p105, therefore, can directly regulate both NF-κB and ERK MAP kinase activation via NF-κB1 p105. TPL-2 is critical for production of the proinflammatory cytokine TNF during inflammatory responses. Consequently, there has been considerable interest in the pharmaceutical industry to develop selective TPL-2 inhibitors as drugs for the treatment of TNF-dependent inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. This review summarizes our current understanding of the regulation of TPL-2 signaling function, and also the complex positive and negative roles of TPL-2 in immune and inflammatory responses.

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Section: Tpl-2 Kinase As An Anti-inflammatory Drug Targetmentioning

confidence: 99%

Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase

Gantke¹,

Sriskantharajah²,

Ley³

2010

Cell Res

130

157

View full text Add to dashboard Cite

show abstract

“…T-and B-cells, DCs) can be overcome by DMARDs such as methotrexate (MTX), sulfasalazine and leflunomide, DMARBDs, such as chimeric and fully humanized anti-TNF-α monoclonal antibodies and anti-TNF-α fusion protein, anti-IL-1 receptor antagonist protein, anti-IL-1 monoclonal antibody or dimeric fusion protein CTLA-4Ig, anti-CD20 monoclonal antibody and anti-IL-6R monoclonal antibody that are now employed in the clinical treatment of RA [97,[149][150][151][152][153][154][155][156][157][158][159][160][161][162][163][164][165]. Two elements from the results of these studies stand out.…”

Section: Apoptotic Responses To Anti-ra Therapiesmentioning

confidence: 99%

Apoptosis Resistance in Rheumatoid Arthritis Synovial Tissue

Malemud¹

2012

J Clin Cell Immunol

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“…It has been shown that IL-1 alone can induce osteoclastogensis but only in osteoclast precursors over-expressing IL-1R1 (Kim et al, 2009). Several in vitro studies show that IL-1 inhibition by natural inhibitors such as IL-1 receptor antagonist or soluble receptors decreases MMP expression and cartilage destruction in OA (Jacques et al, 2006). Macrophages can produce pro-inflammatory cytokine IL-18.…”

Section: Activation Of Monocytes and Macrophages During Oamentioning

confidence: 99%