Interleukin-6 (IL-6) production by astrocytes: Autocrine regulation by IL-6 and the soluble IL-6 receptor

In the CNS, astrocytes are a major inducible source of interleukin-6 (IL-6) . Although IL-6 has beneficial effects in the CNS because of its neurotroph ic properties, its overexpression is generally detrimental, adding to the p athophysiology associated with CNS disorders. Many factors have been shown to induce IL-6 expression by astrocytes, particularly the cytokines tumor n ecrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta). Howeve r, the role of IL-6 in its own regulation in astrocytes has not been determ ined. In this study, we examined the influence of IL-6 alone or in combinat ion with TNF-alpha or IL-1 beta on IL-6 expression. IL-6 alone had no effec t on IL-6 expression; however, the addition of the soluble IL-6 receptor (s IL-6R) induced IL-6 transcripts. Addition of TNF-alpha or IL-1 beta plus IL -6/sIL-6R led to synergistic increases in IL-6 expression. This synergy als o occurred in the absence of exogenously added IL-6, attributable to TNF-al pha- or IL-1 beta-induced endogenous IL-6 protein production. IL-6 upregula tion seen in the presence of TNF-alpha or IL-1 beta plus IL-6/sIL-6R was tr anscriptional, based on nuclear run-on analysis. Experiments were extended to other IL-6 family members to determine their role in IL-6 regulation in astrocytes. Oncostatin M (OSM) induced IL-6 alone and synergized with TNF-a lpha for enhanced expression, These results demonstrate that IL-6/sIL-6R an d OSM play an important role in the regulation of IL-6 expression within th e CNS, particularly in conjunction with the proinflammatory cytokines TNF-a lpha and IL-1 beta.