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

Objective. To examine the patterns of production of interleukin-1 receptor antagonist (IL-1Ra) isoforms and of IL-1 beta during arthritis in vivo. Methods. Arthritis was induced in DBA/1 mice by immunization with type II c ollagen, and the production of IL-1Ra isoforms was examined in whole joints and in dissected synovial tissues by reverse transcription-polymerase chai n reaction (RT-PCR), RNase protection assay, Western blotting, immunostaini ng, and in situ hybridization. Production of IL-1 beta also was examined us ing similar approaches. Results. Production of IL-1Ra increased in the joints during collagen-induc ed arthritis (CIA). By RT-PCR, secreted IL-1Ra messenger RNA (mRNA) was det ected in normal joints, whereas intracellular IL-1Ra type I (icIL-1Ra1) mRN A was only produced in inflamed joints. Western blot studies showed that ic IL-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 a ssays showed that the IL-1 beta :IL-1Ra mRNA ratio was increased in inflame d 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 icI L-1Ra1 was only present in inflamed joints. The histologic evaluation of CI A during the course of the disease indicated a resolution of acute inflamma tion, since icIL-1Ra1 production increased and the ratio of IL-1 beta to to tal IL-1Ra decreased. Conclusion. Production of IL-1Ra isoforms, particularly icIL-1Ra1, is stimu lated in inflamed joints during CIA in mice. The combination of decreased p roduction of IL-1 beta and elevated levels of icIL-1Ra1 during the course o f CIA was associated with a reduction in inflammatory activity. These resul ts suggest that icIL-1Ra1 may play a role in the resolution of murine CIA.