Evidence of an Eicosanoid Contribution to IL-1 Induction of IL-6 in Human Articular Chondrocytes.
It has been demonstrated previously that interleukin-1 (IL-1) induces articular cartilage explants and chondrocytes in culture to produce elevated levels of inflammatory mediators such as interleukin-6 (IL-6) and prostaglandins. Previous studies have also demonstrated a relationship between IL-6 secretion and the ability of IL-1 to modulate proteoglycan synthesis by chondrocytes. In this study we have utilized an alginate culture system in an effort to investigate a role for eicosanoids in IL-1 induction of IL-6 expression in human articular chondrocytes. IL-1 treatment of chondrocytes cultured in alginate resulted in increased synthesis of IL-6 and prostaglandins, but not leukotrienes. Cyclo-oxygenase inhibitor, indomethacin (5 &mgr;g ml(minus sign1)), was able to inhibit prostaglandin synthesis to below basal levels with no significant effect on the levels of IL-6 released by chondrocytes in response to IL-1. When chondrocytes were treated with 5 &mgr;g ml(minus sign1) indomethacin and 10 &mgr;M of the general lipoxygenase inhibitor, nordihydroguiaretic acid (NDGA), an approximate 50% decrease in IL-1-induced IL-6 expression was observed. Alone, levels of NDGA specific for lipoxygenase inhibition (10 &mgr;M) did not affect IL-1-induced IL-6 expression, but higher levels of NDGA (50 &mgr;M) which inhibited both prostaglandin and leukotriene biosynthesis reduced IL-1-induced IL-6 expression to the same extent as that observed with 5 &mgr;g ml(minus sign1) indomethacin and 10 &mgr;M NDGA. This inhibition of IL-6 expression by NDGA and indomethacin was dose responsive and also reversible with the addition of exogenous prostaglandin E(2) (PGE(2)) or leukotriene B(4) (LTB(4)). Although IL-1-induced IL-6 expression was only affected when both prostaglandin and leukotriene biosynthesis were inhibited, elevated levels of PGE(2) but not leukotriene B(4), C(4), D(4), or E(4) were observed in the culture medium of IL-1-treated chondrocytes. These findings may indicate that cyclo-oxygenase products such as PGE(2) normally contribute to IL-1 induction of IL-6 expression in chondrocytes, and under conditions when cyclo-oxygenase is inhibited, lipoxygenase products alternatively contribute to this response.
Clausen
Peter A.
PA
Department of Biochemistry, Rush Pressbyterian--St. Luke's Medical Center, Chicago, USA.
Flechtenmacher
Johannes
J
Haeuselmann
Hans J.
HJ
Kuettner
Klaus E.
KE
Aydelotte
Margaret B.
MB
Iyer
Anand P.
AP