Inhibition of IL-6 signaling by a p38-dependent pathway occurs in the absence of new protein synthesis

Simi T. Ahmed, Alexander Mayer, Jong Dae Ji, Lionel B. Ivashkiv

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)


Negative regulation of cytokine signaling is important for limiting the intensity and duration of cytokine action and for maintaining homeostasis. Several constitutive mechanisms for suppressing cytokine Jak-STAT signaling have been described. Inducible or regulated inhibition of cytokine signaling is equally important, and much attention has been focused on inhibition mediated through the induction of expression of suppressors of cytokine signaling (SOCS proteins). We have previously reported IL-1-induced inhibition of IL-6 signaling in monocytes, and herein we use inhibitors of protein synthesis to demonstrate that inhibition of IL-6 signaling can occur in the absence of new protein synthesis. Surprisingly, some protein synthesis inhibitors themselves inhibited IL-6 signaling rapidly, strengthening the conclusion that IL-6 signaling can be inhibited in the absence of protein synthesis. Inhibition of IL-6 signaling by IL-1 and protein synthesis inhibitors was dependent on the p38 stress kinase, and activation of p38 secondary to inducible expression of MKK6 was sufficient to inhibit IL-6 signaling. Inhibition was specific for IL-6, as induction of STAT activation by IFN-γ, IFN-α, and vanadate was not inhibited. IL-1-induced inhibition of IL-6 signaling was not mediated by the activation of tyrosine phosphatases or by p38-dependent activation of phospholipase A2 or cyclooxygenases, which could lead to indirect inhibition via production of prostaglandins. These results identify an inducible mechanism of inhibition of IL-6 signaling that is direct and independent of induction of negative regulators such as SOCS proteins. A role for p38 in mediating inhibition suggests that multiple cytokines and stress agents that activate p38 pathways in monocytes, such as IL-1, TNF, Toll-like receptors, and Fc receptors, can modulate Jak-STAT signaling by pleiotropic cytokines such as IL-6.

Original languageEnglish
Pages (from-to)154-162
Number of pages9
JournalJournal of Leukocyte Biology
Issue number1
Publication statusPublished - 2002 Jul 1
Externally publishedYes


  • Cytokines
  • Monocytes/macrophages
  • Signal transduction

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology


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