Interleukin 10 modulation of tumour necrosis factor receptors requires tyrosine kinases but not the PI 3-kinase/p70 S6 kinase pathway

We have previously shown that interleukin (IL-) 10-induced proliferation of the murine mast cell line D36, was dependent upon the activation of PI 3-k inase and p70 S6 kinase, Conversely, we were able to show that this pathway was not involved in the signal transduction pathway mediating IL-10 inhibi tion of pro-inflammatory cytokine release from monocytes. We have extended these studies to investigate the induction of p75 tumour necrosis factor re ceptor (TNF-R) shedding, another anti-inflammatory property of IL-10, Using the inhibitors of PI 3-kinase (LY294002 and wortmannin) and an inhibitor o f p70 SG kinase activation (rapamycin), we were able to show that this anti -inflammatory effect of IL-10 was not mediated by the PI 3-kinase/p70 S6 ki nase pathway, indicating that another signalling cascade(s) was involved, F urther studies also investigated the role of tyrosine kinases in the respon se to IL-10, Two distinct tyrosine kinase inhibitors, herbimycin and genist ein affected the expression of TNF-R in response to IL-10 but, surprisingly , with opposite effects, However, both compounds inhibited the activation o f both PI 3-kinase and p70 S6 kinase, with a concomitant inhibition of IL-1 0-induced proliferation. We observed that whilst tyrosine kinase activity w as involved in the regulation of TNF-R expression, IL-10-induced activation of JAK kinases was not sensitive to inhibition by the tyrosine kinase inhi bitors. These data suggest that multiple unknown tyrosine kinases are media ting the IL-10-induced signal transduction pathways leading to the regulati on of TNF-R expression and IL-10-induced proliferation. (C) 2000 Academic P ress.