The effects of interleukin-18 on rat articular chondrocytes: a study of mRNA expression and protein synthesis of proinflammatory substances.
Interleukin (IL)-18 is a potent stimulator of immunity and augments the severity of type II collagen-induced arthritis (CIA) in rats and mice by enhancing T helper 1 (Th1) cell activation, which increases the production of proinflammatory cytokines and arthritogenic antibodies. In this study, we show that recombinant IL-18 (rIL-18) also has a direct effect on normal rat chondrocytes maintained in vitro inducing them to produce proinflammatory factors including IL-6, regulated upon activation normal T cell expressed and secreted (RANTES), prostaglandin E(2) (PGE(2)) and prostaglandin F(2alpha) (PGF(2alpha)) in a dose- and time-dependent manner. The production of matrix metalloproteinase (MMP)-13, nitric oxide (NO), tumour necrosis factor (TNF)-alpha and IL-1beta were also enhanced, although less intensely. Neutralizing polyclonal anti-rIL-18 antibodies effectively blocked the production of IL-6, PGE(2) and RANTES, as well as mRNA expression for the same products in addition to IL-18 and TNF-alpha. In contrast, neutralizing antibodies to IL-1beta, TNF-alpha and IL-6 were ineffective in suppressing any of these products. Together, these findings suggest that IL-18 may play an important, possibly direct, role in mediating cartilage injury, which might not be amenable to treatment with currently utilized anti-cytokine agents. These findings suggest further that IL-18 antagonists might prove beneficial as anti-inflammatory and chondroprotective agents in the treatment of arthritis, and that the development of such agents for human use is worth consideration.
Ye
X J
XJ
Department of Medicine, University of Tennessee Health Science Centers, Memphis, TN, USA.
Tang
B
B
Ma
Z
Z
Zhou
J
J
Myers
L K
LK
Kang
A H
AH
Cremer
M A
MA
D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology / Q000276:immunology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D005786:Gene Expression Regulation / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism*; D020382:Interleukin-18 / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011913:Rats, Inbred BB; D011994:Recombinant Proteins / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D018836:Inflammation Mediators; D020382:Interleukin-18; D012333:RNA, Messenger; D011994:Recombinant Proteins