Differential effects of IL-8, LIF (pro-inflammatory) and IL-11 (anti-inflammatory) on TNF-alpha-induced PGE(2) release and on signalling pathways in human OA synovial fibroblasts

Tumour necrosis factor alpha (TNF-alpha) inflammatory activity is mediated, at least in part,by prostaglandin E-2 (PGE(2)), In osteoarthritis (OA), ot her cytokines are believed to play a role by interacting with TNF-alpha. Us ing OA synovial fibroblasts, we investigated the effects of interleukin 8 ( IL-8), leukaemia inhibitory factor (LIF) and IL-11 on the level of TNF-alph a-induced PGE(2), and their impact on the TNF-alpha-induced cellular signal ling cascades including the! TNF-receptor (TNF-R), soluble TNF-R (TNF-sR), cytoplasmic phospholipase A2 (cPLA2), cyclooxygenase 2 (COX-2), and the tra nscription factors NF-kappa B, C/EBP, CREB and AP-1. IL-8 increased in a synergistic manner (282% at 5 ng/ml) and LIF in an addi tive fashion (69% at 50 ng/ml) the TNF-alpha-induced PGE(2) release, while IL-11 reduced it (52% at 5 ng/ml), IL-8 (5 ng/ml) and LIF (50 ng/ml) alone upregulated (30%) the TNF-R binding level, but significantly downregulated the TNF-alpha-induced levels (P<0.007 and P<0.004, respectively) and the TN F-sR55 level. In contrast, IL-11 reduced the basal level by 18% (P<0.005) a nd the TNF-alpha-induced level of TNF-R by 51% (P<0.01) as well as decreasi ng both TNF-sR55 and TNF-sR75, The COX;2 synthesis level was increased by I L-8 and LIF under TNF-alpha treatment but downregulated by IL-11. IL-8 and LIF either alone or under TNF-alpha treatment increased the cPLA2 synthesis , while IL-11 decreased the level under both conditions. interestingly, IL- 8 induced in a synergistic manner and LIF in an additive fashion, the level of cPLA2 activity. IL-8 and LIF had no effect on the TNF-alpha-induced NF- kappa B accumulation, while IL-11 significantly decreased it (P<0.02). All three cytokines inhibited TNF-alpha-induced C/EBP, but no true effect was n oted for AP-1 and CREB in the presence of TNF-alpha. These results indicate that IL-8 synergizes and LIF potentiates the TNF-alp ha PGE(2) effect which appears to be mediated mostly by increasing cPLA2 ac tivity level. On the other hand, IL-11 alone had no effect on the PGE(2) re lease, but in conjunction with TNF-alpha, this cytokine showed anti-inflamm atory properties. This study provides a rational foundation to develop ther apeutic strategies for the treatment of OA by shedding light on the mechani sms of action of three prominent cytokines at work in articular joint tissu es. (C) 1999 Academic Press.