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-1beta 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-1beta 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-1beta: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-1beta to total IL-1Ra decreased.


CONCLUSIONS
Production of IL-1Ra isoforms, particularly icIL-1Ra1, is stimulated in inflamed joints during CIA in mice. The combination of decreased production of IL-1beta 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.
Division of Rheumatology, University Hospital of Geneva, Switzerland.
C
C
Gabay
L
L
Marinova-Mutafchieva
R O
RO
Williams
J P
JP
Gigley
D M
DM
Butler
M
M
Feldmann
W P
WP
Arend
D000818:Animals; D001169:Arthritis, Experimental / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000503:physiopathology; D003094:Collagen / Q000276:immunology; D007150:Immunohistochemistry; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000096:biosynthesis; D007596:Joints / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D020033:Protein Isoforms / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D012795:Sialoglycoproteins / Q000096:biosynthesis* / Q000235:genetics; D013583:Synovial Membrane / Q000378:metabolism*
C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D020033:Protein Isoforms; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D003094:Collagen