A proinflammatory role for IL-18 in rheumatoid arthritis.
IL-18 is a novel cytokine with pleiotropic activities critical to the development of T-helper 1 (Th1) responses. We detected IL-18 mRNA and protein within rheumatoid arthritis (RA) synovial tissues in significantly higher levels than in osteoarthritis controls. Similarly, IL-18 receptor expression was detected on synovial lymphocytes and macrophages. Together with IL-12 or IL-15, IL-18 induced significant IFN-gamma production by synovial tissues in vitro. IL-18 independently promoted GM-CSF and nitric oxide production, and it induced significant TNF-alpha synthesis by CD14(+) macrophages in synovial cultures; the latter effect was potentiated by IL-12 or IL-15. TNF-alpha and IFN-gamma synthesis was suppressed by IL-10 and TGF-beta. IL-18 production in primary synovial cultures and purified synovial fibroblasts was, in turn, upregulated by TNF-alpha and IL-1beta, suggesting that monokine expression can feed back to promote Th1 cell development in synovial membrane. Finally, IL-18 administration to collagen/incomplete Freund's adjuvant-immunized DBA/1 mice facilitated the development of an erosive, inflammatory arthritis, suggesting that IL-18 can be proinflammatory in vivo. Together, these data indicate that synergistic combinations of IL-18, IL-12, and IL-15 may be of importance in sustaining both Th1 responses and monokine production in RA.
Gracie
J A
JA
Centre for Rheumatic Diseases, University of Glasgow, Glasgow G31 2ER, United Kingdom.
Forsey
R J
RJ
Chan
W L
WL
Gilmour
A
A
Leung
B P
BP
Greer
M R
MR
Kennedy
K
K
Carter
R
R
Wei
X Q
XQ
Xu
D
D
Field
M
M
Foulis
A
A
Liew
F Y
FY
McInnes
I B
IB
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D017252:CD3 Complex / Q000032:analysis; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000235:genetics; D018664:Interleukin-12 / Q000494:pharmacology; D019409:Interleukin-15 / Q000494:pharmacology; D020382:Interleukin-18 / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D053727:Interleukin-18 Receptor alpha Subunit; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D010003:Osteoarthritis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D018123:Receptors, Interleukin / Q000032:analysis / Q000235:genetics; D053724:Receptors, Interleukin-18; D013582:Synovial Fluid / Q000737:chemistry / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D017252:CD3 Complex; C508572:IL18R1 protein, human; C508573:Il18r1 protein, mouse; D019409:Interleukin-15; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma