Dual function of interleukin-1β for the regulation of interleukin-6-induced suppressor of cytokine signaling 3 expression

Abstract

Interleukin-6 (IL-6) exerts pro- as well as anti-inflammatory activities in response to infection, injury, or other stimuli that affect the homeostasis of the organism. IL-6-induced expression of acute-phase protein genes in the liver is tightly regulated through both IL-6-induced feedback inhibitors and the activity of proinflammatory cytokines such as tumor necrosis factor a and interleukin-1β. In previous studies mechanisms for how IL-1β counteracts IL-6-dependent acute-phase protein gene induction have been proposed. Herein we analyzed IL-1β-mediated regulation of IL-6-induced expression of the feedback inhibitor SOCS3. In hepatocytes IL-1β alone does not induce SOCS3 expression, but it counteracts SOCS3-promoter activation in long term studies. Surprisingly, short term stimulation revealed IL-1β to be a potent enhancer of SOCS3 expression in concert with IL-6. This activity of IL-1β does not depend on IL-1β-dependent STAT1-serine phosphorylation but on NF-κB-dependent gene induction. Such a regulatory network allows IL-1β to counteract IL-6-dependent expression of acute-phase protein genes without inhibiting IL-6-induced SOCS3 expression and provides a reasonable mechanism for the IL-1β-dependent inhibition of acute-phase gene induction, because reduced SOCS3 expression would lead to enhanced IL-6 activity.