The pivotal role of interleukin-1 in the clinical manifestations of rheumatoid arthritis

Dayer, Jean‐Michel

doi:10.1093/rheumatology/keg326

Cited by 150 publications

(134 citation statements)

References 48 publications

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“…Because IL-1 (but not TNF or type I or II IFNs) appears to be essential for the development of inflammatory disease in spin homozygotes, MyD88 deficiency may suppress the spin phenotype by preventing IL-1 signaling. IL-1 signaling is known to be an essential element in the development of several severe inflammatory diseases, including NOMID, familial cold autoinflammatory syndrome (4), and certain cases of rheumatoid arthritis (28). We suggest here that it also mediates disease observed in mice with hypomorphic mutations affecting SHP1.…”

Section: Discussionmentioning

confidence: 74%

Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger

Croker

Lawson

Berger

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

104

126

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A recessive phenotype called spin (spontaneous inflammation) was induced by N -ethyl- N -nitrosourea (ENU) mutagenesis in C57BL/6J mice. Homozygotes display chronic inflammatory lesions affecting the feet, salivary glands and lungs, and antichromatin antibodies. They are immunocompetent and show enhanced resistance to infection by Listeria monocytogenes . TLR-induced TNF and IL-1 production are normal in macrophages derived from spin mice. The autoinflammatory phenotype of spin mice is fully suppressed by compound homozygosity for Myd88 poc , Irak4 otiose , and Il1r1 -null mutations, but not Ticam1 Lps2 , Stat1 m1Btlr , or Tnf -null mutations. Both autoimmune and autoinflammatory phenotypes are suppressed when spin homozygotes are derived into a germ-free environment. The spin phenotype was ascribed to a viable hypomorphic allele of Ptpn6 , which encodes the tyrosine phosphatase SHP1, mutated in mice with the classical motheaten alleles me and me-v . Inflammation and autoimmunity caused by SHP1 deficiency are thus conditional. The SHP1-deficient phenotype is driven by microbes, which activate TLR signaling pathways to elicit IL-1 production. IL-1 signaling via MyD88 elicits inflammatory disease.

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Section: Discussionmentioning

confidence: 74%

Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger

Croker

Lawson

Berger

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

104

126

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“…This cell type was shown to be unable to produce enough IL-1Ra to counteract IL-1 during the course of RA (13,30) and to be highly responsive to IL-1␤, which plays a key pathophysiologic role in arthritis (1). Under these exper-imental conditions, we showed an opposite effect of PPAR␥ agonists on the expression and secretion of IL-1Ra as well as on the balance between IL-1␤ and IL-1Ra.…”

mentioning

confidence: 67%

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

Moulin¹,

Bianchi²,

Boyault³

et al. 2005

Arthritis & Rheumatism

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Objective. To study the potency of 2 peroxisome proliferator-activated receptor ␥ (PPAR␥) agonists, 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15-deoxy-PGJ 2 ) and rosiglitazone, to modulate the expression of interleukin-1 receptor antagonist (IL-1Ra) in rat synovial fibroblasts.Methods. Levels of messenger RNA for IL-1Ra and PPAR isotypes (␣, ␤/␦, ␥) were assessed by realtime polymerase chain reaction in rat synovial fibroblasts exposed to 10 ng/ml of IL-1␤. PPAR levels were assessed by Western blotting and secreted IL-1Ra levels by immunoassay. The potency of PPAR␥ agonists and the PPAR␤/␦ agonist GW-501516 on IL-1Ra levels was tested in the range of 1-10 M and at 100 pM, respectively. The contribution of PPAR␥ to the effects of rosiglitazone on IL-1Ra secretion was examined either by its overexpression or by inhibition using wild-type or dominant-negative constructs and the antagonist GW-9662 (10 M), respectively. The dominant-negative strategy was also performed to investigate the possible contribution of PPAR␤/␦ and NF-B activation.Results. IL-1␤-induced IL-1Ra production was increased by 10 M rosiglitazone but was reduced dose-dependently by 15-deoxy-PGJ 2 . Both agonists lowered IL-1␤ secretion, but rosiglitazone alone reduced the imbalance of IL-1␤/IL-1Ra toward basal levels. Enhancement of IL-1␤-induced IL-1Ra production by rosiglitazone was not affected by PPAR␥ overexpression or by its inhibition with dominant-negative PPAR␥ or GW-9662. Inhibition of NF-B was also ineffective against rosiglitazone but abolished the stimulating effect of IL-1␤ on IL-1Ra. All PPAR isotypes were expressed constitutively in rat synoviocytes, but PPAR␥ decreased dramatically upon IL-1␤ exposure, whereas PPAR␤/␦ remained stable. Dominant-negative PPAR␤/␦ abolished the enhancement of IL-1Ra by rosiglitazone, whereas GW-501516 reproduced the effect of rosiglitazone on IL-1Ra secretion.Conclusion. Rosiglitazone stimulates IL-1Ra production by a PPAR␤/␦ mechanism in activated rat synovial fibroblasts, further contributing to its potential antiarthritic properties and opening new perspectives for the modulation of inflammatory genes by specific PPAR agonists in articular cells.

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“…In fact, many of them directly trigger negative feedback loops, including synthesis of antiinflammatory cytokines such as . Certain cytokine and chemokine proteins are synthesized as proforms (IL-1␤) or membranebound precursors (TNF␣), requiring proteolysis for activation (9,10). Secreted IL-1␤ can be sequestered by a decoy receptor (IL-1RII) or a soluble receptor antagonist (IL-1Ra), precluding it from signaling (10).…”

mentioning

confidence: 99%

“…Certain cytokine and chemokine proteins are synthesized as proforms (IL-1␤) or membranebound precursors (TNF␣), requiring proteolysis for activation (9,10). Secreted IL-1␤ can be sequestered by a decoy receptor (IL-1RII) or a soluble receptor antagonist (IL-1Ra), precluding it from signaling (10). mRNAs encoding many proinflammatory mediators are intrinsically unstable because of the AU-rich elements (AREs) that bind proteins like tristetraprolin (TTP), which target the transcripts for mRNA decay (11); TNF␣, IL-6, IL-1␤, and IL-10 are all thought to be subject to TTP-mediated degradation (12,13).…”

mentioning

confidence: 99%

Immediate mediators of the inflammatory response are poised for gene activation through RNA polymerase II stalling

Adelman

Kennedy

Nechaev

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

141

140

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The kinetics and magnitude of cytokine gene expression are tightly regulated to elicit a balanced response to pathogens and result from integrated changes in transcription and mRNA stability. Yet, how a single microbial stimulus induces peak transcription of some genes (TNF␣) within minutes whereas others (IP-10) require hours remains unclear. Here, we dissect activation of several lipopolysaccharide (LPS)-inducible genes in macrophages, an essential cell type mediating inflammatory response in mammals. We show that a key difference between the genes is the step of the transcription cycle at which they are regulated. Specifically, at TNF␣, RNA Polymerase II initiates transcription in resting macrophages, but stalls near the promoter until LPS triggers rapid and transient release of the negative elongation factor (NELF) complex and productive elongation. In contrast, no NELF or polymerase is detectible near the IP-10 promoter before induction, and LPS-dependent polymerase recruitment is rate limiting for transcription. We further demonstrate that this strategy is shared by other immune mediators and is independent of the inducer and signaling pathway responsible for gene activation. Finally, as a striking example of evolutionary conservation, the Drosophila homolog of the TNF␣ gene, eiger, displayed all of the hallmarks of NELF-dependent polymerase stalling. We propose that polymerase stalling ensures the coordinated, timely activation the inflammatory gene expression program from Drosophila to mammals. cytokine gene expression ͉ inflammation ͉ TNF␣ ͉ transcription initiation and elongation ͉ NELF

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The pivotal role of interleukin-1 in the clinical manifestations of rheumatoid arthritis

Cited by 150 publications

References 48 publications

Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger

Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

Immediate mediators of the inflammatory response are poised for gene activation through RNA polymerase II stalling

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