
Increased production of intracellular interleukin‐1 receptor antagonist type I in the synovium of mice with collagen‐induced arthritis: A possible role in the resolution of arthritis
Author(s) -
Gabay Cem,
MarinovaMutafchieva Liliana,
Williams Richard O.,
Gigley Jason P.,
Butler Debra M.,
Feldmann Marc,
Arend William P.
Publication year - 2001
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/1529-0131(200102)44:2<451::aid-anr64>3.0.co;2-h
Subject(s) - arthritis , in situ hybridization , gene isoform , messenger rna , biology , blot , microbiology and biotechnology , intracellular , receptor antagonist , inflammation , interleukin , western blot , northern blot , type ii collagen , immunology , receptor , antagonist , cytokine , biochemistry , gene
Objective To examine the patterns of production of interleukin‐1 receptor antagonist (IL‐1Ra) isoforms and of IL‐1β during arthritis in vivo. Methods Arthritis was induced in DBA/1 mice by immunization with type II collagen, and the production of IL‐1Ra isoforms was examined in whole joints and in dissected synovial tissues by reverse transcription–polymerase chain reaction (RT‐PCR), RNase protection assay, Western blotting, immunostaining, and in situ hybridization. Production of IL‐1β also was examined using similar approaches. Results Production of IL‐1Ra increased in the joints during collagen‐induced arthritis (CIA). By RT‐PCR, secreted IL‐1Ra messenger RNA (mRNA) was detected in normal joints, whereas intracellular IL‐1Ra type I (icIL‐1Ra1) mRNA was only produced in inflamed joints. Western blot studies showed that icIL‐1Ra1 protein levels increased in the joints during the course of CIA and that icIL‐1Ra3 protein was also present in low amounts. RNase protection assays showed that the IL‐1β:IL‐1Ra mRNA ratio was increased in inflamed joints through day 14 of arthritis, whereas a reverse pattern was present at later time points (from day 20 to day 60). Consistent with this finding, immunohistochemistry and in situ hybridization studies confirmed that icIL‐1Ra1 was only present in inflamed joints. The histologic evaluation of CIA during the course of the disease indicated a resolution of acute inflammation, since icIL‐1Ra1 production increased and the ratio of IL‐1β to total IL‐1Ra decreased. Conclusion Production of IL‐1Ra isoforms, particularly icIL‐1Ra1, is stimulated in inflamed joints during CIA in mice. The combination of decreased production of IL‐1β and elevated levels of icIL‐1Ra1 during the course of CIA was associated with a reduction in inflammatory activity. These results suggest that icIL‐1Ra1 may play a role in the resolution of murine CIA.