Evidence for the biological modulation of IL-1 activity: the role of IL-1Ra.
Interleukin-1 (IL-1) and tumor necrosis factor (TNFalpha) are key mediators of inflammation and are produced by monocyte-macrophages (Mphi) following the activation of soluble factors and contact with stimulated Th1 lymphocytes. The contact between lymphocytes and Mphi is regulated by ligand and counterligands (i.e. beta2-integrins, CD40-CD40L, CD69) and plasma lipoproteins (i.e. HDL-associated Apo-AI). IL-1 and TNFalpha are potent inducers of matrix metalloproteinases (MMPs), eicosanoids, nitric oxide oxydase (iNOS), receptor activator of NF-kappaB ligand (RANKL), products involved in the destruction of the extracellular matrix, the cartilage and in bone resorption. IL-1--particularly important at the local level--is more potent than TNF in stimulating MMPs and specifically in impeding cartilage repair. However, IL-1 and TNFalpha strongly synergize in multiple biological functions. Blockade of IL-1 by IL-1 receptor antagonist (IL-1Ra, sIL-1RII) in combination with the soluble IL-1 accessory protein (IL-1R AcP) result in a long-term beneficial effect in chronic inflammatory diseases. The association with anti-TNF therapy may also represent a logical approach, considering the number of patients that do not respond to either compound alone. An altogether new challenge would be to accomplish the blockade at a more proximal level (i.e. lymphocyte/Mphi interaction).
Division of Immunology & Allergy, University Hospital, Geneva, Switzerland. Jean-Michel.Dayer@hcuge.ch
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Dayer
D000818:Animals; D016525:Antigenic Modulation / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000503:physiopathology; D002450:Cell Communication / Q000276:immunology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000276:immunology*; D051379:Mice; D023421:Models, Animal; D051381:Rats; D012795:Sialoglycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha