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*
Graduate Program in Immunology, Weill Graduate School of Medical Sciences, and
Department of Medicine, Hospital for Special Surgery, Weill Medical College of Cornell University, New York, NY 10021
The development and resolution of an inflammatory process are
regulated by a complex interplay among cytokines that have pro- and
anti-inflammatory effects. Effective and sustained action of a
proinflammatory cytokine depends on synergy with other inflammatory
cytokines and antagonism of opposing cytokines that are often highly
expressed at inflammatory sites. We analyzed the effects of the
inflammatory and stress agents, IL-1, TNF-
, LPS, sorbitol, and
H2O2, on signaling by IL-6 and IL-10,
pleiotropic cytokines that activate the Jak-Stat signaling pathway and
have both pro- and anti-inflammatory actions. IL-1, TNF-, and
LPS blocked the activation of Stat DNA binding and tyrosine
phosphorylation by IL-6 and IL-10, but not by IFN-
, in primary
macrophages. Inhibition of Stat activation correlated with inhibition
of expression of IL-6-inducible genes. The inhibition was rapid and
independent of de novo gene induction and occurred when the expression
of suppressor of cytokine synthesis-3 was blocked. Inhibition of IL-6
signaling was mediated by the p38 subfamily of stress-activated protein
kinases. Jak1 was inhibited at the level of tyrosine phosphorylation,
indicating that inhibition occurred at least in part upstream of Stats
in the Jak-Stat pathway. Experiments using Stat3 mutated at serine 727
and using truncated IL-6Rs suggested that the target of inhibition is
contained within the membrane-proximal region of the cytoplasmic domain
of the gp130 subunit of the IL-6 receptor and is different from the SH2
domain-containing protein-tyrosine phosphatase/suppressor of cytokine
synthesis-3 docking site. These results identify a new level at which
IL-1 and TNF- modulate signaling by pleiotropic cytokines such as
IL-6 and IL-10 and provide a molecular basis for the previously
described antagonism of certain IL-6 actions by
IL-1.
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