Reversal of autocrine and paracrine effects of interleukin 1 (IL-1) in human arthritis by type II IL-1 decoy receptor. Potential for pharmacological intervention.
Interleukin 1 (IL-1), produced by both synovial cells and chondrocytes, plays a pivotal role in the pathogenesis of cartilage destruction in osteoarthritis (OA). We examined the specific expression and function of IL-1 receptor family-related genes in human joint tissues. Gene array analysis of human normal and OA-affected cartilage showed mRNA expression of IL-1 receptor accessory protein (IL-1RAcp) and IL-1 type I receptor (IL-1RI), but not IL-1 antagonist (IL-1ra) and IL-1 type II decoy receptor (IL-1RII). Similarly, human synovial and epithelial cells showed an absence of IL-1RII mRNA. Functional genomic analyses showed that soluble (s) IL-1RII, at picomolar concentrations, but not soluble TNF receptor:Fc, significantly inhibited IL-1beta-induced nitric oxide (NO) and/or prostaglandin E(2) production in chondrocytes, synovial and epithelial cells. In OA-affected cartilage, the IC(50) for inhibition of NO production by sIL-1RII was 2 log orders lower than that for sIL-1RI. Human chondrocytes that overexpressed IL-1RII were resistant to IL-1-induced IL-1beta mRNA accumulation and inhibition of proteoglycan synthesis. In osteoarthritis, deficient expression by chondrocytes of innate regulators or antagonists of IL-1 such as IL-1ra and IL-1RII (soluble or membrane form) may allow the catabolic effects of IL-1 to proceed unopposed. The sensitivity of IL-1 action to inhibition by sIL-1RII has therapeutic implications that could be directed toward correcting this unfavorable tissue(s) dependent imbalance.
Attur
M G
MG
Department of Rheumatology, Hospital for Joint Diseases, New York, New York 10003, USA.
Dave
M
M
Cipolletta
C
C
Kang
P
P
Goldring
M B
MB
Patel
I R
IR
Abramson
S B
SB
Amin
A R
AR
D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism / Q000503:physiopathology; D002417:Cattle; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D015232:Dinoprostone / Q000096:biosynthesis; D005786:Gene Expression Regulation; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis; D010003:Osteoarthritis / Q000188:drug therapy / Q000503:physiopathology*; D011509:Proteoglycans / Q000096:biosynthesis; D017472:Receptors, Interleukin-1 / Q000502:physiology*; D013583:Synovial Membrane / Q000378:metabolism
D007375:Interleukin-1; D011509:Proteoglycans; D017472:Receptors, Interleukin-1; D009569:Nitric Oxide; D015232:Dinoprostone