The role of IL-1 and IL-1Ra in joint inflammation and cartilage degradation.
Interleukin (IL)-1 is a cytokine that plays a major role in inflammatory responses in the context of infections and immune-mediated diseases. IL-1 refers to two different cytokines, termed IL-1alpha and IL-1beta, produced from two genes. IL-1alpha and IL-1beta are produced by different cell types following stimulation by bacterial products, cytokines, and immune complexes. Monocytes/macrophages are the primary source of IL-1beta. Both cytokines do not possess leader peptide sequences and do not follow a classical secretory pathway. IL-1alpha is mainly cell associated, whereas IL-1beta can be released from activated cells after cleavage of its amino-terminal region by caspase-1. IL-1 is present in the synovial tissue and fluids of patients with rheumatoid arthritis. Several in vitro studies have shown that IL-1 stimulates the production of mediators such as prostaglandin E(2), nitric oxide, cytokines, chemokines, and adhesion molecules that are involved in articular inflammation. Furthermore, IL-1 stimulates the synthesis and activity of matrix metalloproteinases and other enzymes involved in cartilage destruction in rheumatoid arthritis and osteoarthritis. The effects of IL-1 are inhibited in vitro and in vivo by natural inhibitors such as IL-1 receptor antagonist and soluble receptors. IL-1 receptor antagonist belongs to the IL-1 family of cytokines and binds to IL-1 receptors but does not induce any intracellular response. IL-1 receptor antagonist inhibits the effect of IL-1 by blocking its interaction with cell surface receptors. The use of IL-1 inhibitors in experimental models of inflammatory arthritis and osteoarthritis has provided a strong support for the role of IL-1 in the pathogeny of these diseases. Most importantly, these findings have been confirmed in clinical trials in patients with rheumatic diseases. Additional strategies aimed to block the effect of IL-1 are tested in clinical trials.
Jacques
Claire
C
UMR 7079 CNRS, Physiology and Physiopathology Laboratory, University Paris 6, Paris, 75252 Cedex 5, France.
Gosset
Marjolaine
M
Berenbaum
Francis
F
Gabay
Cem
C
D000818:Animals; D001168:Arthritis / Q000276:immunology*; D002358:Cartilage, Articular / Q000276:immunology* / Q000473:pathology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000276:immunology*; D053582:Interleukin-1alpha / Q000276:immunology*; D007596:Joints / Q000276:immunology*; D051379:Mice; D010007:Osteochondritis / Q000276:immunology; D011817:Rabbits; D051381:Rats; D012216:Rheumatic Diseases / Q000276:immunology*
D053590:Interleukin 1 Receptor Antagonist Protein; D053582:Interleukin-1alpha