IL-18 is redundant in T-cell responses and in joint inflammation in antigen-induced arthritis.
IL-18 is an important cofactor in Th1 immune responses and it has additional roles in inflammation. Recent reports suggest the contribution of IL-18 to immune responses may vary between mouse strains and immune contexts. We investigated the contribution of IL-18 to T-cell activation and joint inflammation in Ag-induced arthritis (AIA) in C57Bl/6 mice. AIA and cutaneous delayed-type hypersensitivity (DTH) reactions were induced in wild-type (WT) and IL-18-/- C57Bl/6 mice, and Ag-specific T-cell proliferation and IFN-gamma and IL-4 production were measured. The humoral immune response was measured as serum antibody to the disease-initiating Ag, methylated BSA (mBSA). Splenocyte production of IL-6 was measured by ELISA. To confirm the dependence of this model on Th1-cell-mediated immunity, IL-12p40-/- mice were similarly studied. WT mice developed synovitis, joint effusion, cartilage destruction and bone damage associated with induction of DTH, and in vitro Ag-specific T-cell proliferation and IFN-gamma production. Unexpectedly, IL-18-/- mice developed AIA and indices of T-cell activation were similar to those of WT mice. In contrast, IL-12p40-/- mice did not develop AIA, DTH or T-cell activation. WT and IL-18-/- mice, but not IL-12p40-/- mice, developed significantly increased serum antibody to mBSA compared with naive controls. WT and IL-18-/- splenocytes produced high levels of IL-6, whereas IL-12p40-/- cells had significantly lower IL-6 production compared with both. In conclusion, IL-18 is redundant both as a Th1 response cofactor and inflammatory cytokine, whereas IL-12p40-/- is a key cytokine, in AIA in C57Bl/6 mice.
Santos
Leilani L
LL
Centre for Inflammatory Diseases, Monash Institute of Medical Research, Monash Medical Centre, Melbourne, Australia. lanie.santos@med.monash.edu.au
Milenkovski
Georgia P
GP
Hall
Pamela H
PH
Leech
Michelle
M
Sharma
Laveena
L
Takeda
Kiyoshi
K
Akira
Shizuo
S
Kitching
A Richard
AR
Morand
Eric F
EF
D000818:Animals; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D013045:Species Specificity; D013585:Synovitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology
D001323:Autoantibodies; D001324:Autoantigens; D016207:Cytokines; D020382:Interleukin-18