The multikinase inhibitor Sorafenib reverses the suppression of IL-12 and enhancement of IL-10 by PGE2 in murine macrophages

Justin P. Edwards, Leisha A. Emens

Research output: Contribution to journalArticle

Abstract

Classical activating stimuli like LPS drive macrophages to secrete a battery of inflammatory cytokines, including interleukin (IL)-12/23, through Toll-like receptor (TLR) signaling. TLR activation in the presence of some factors, including prostaglandin E2 (PGE2), promotes an anti-inflammatory cytokine profile, with production of IL-10 and suppression of IL-12/23 secretion. Extracellular signal-regulated kinase (ERK) is a key regulator of macrophage IL-10 production. Since it inhibits ERK, we investigated the impact of Sorafenib on the cytokine profile of macrophages. In the presence of PGE2, Sorafenib restored the secretion of IL-12 and suppressed IL-10 production. Moreover, IL-12 secretion was enhanced by Sorafenib under conditions of TLR ligation alone. Furthermore, the impact of tumor culture supernatants, cholera toxin, and cAMP analogs (which suppress IL-12 secretion), was reversed by Sorafenib. Sorafenib inhibited the activation of the MAP kinase p38 and its downstream target mitogen and stress activated protein kinase (MSK), and partially inhibited protein kinase B (AKT) and its subsequent inactivation of the downstream target glycogen synthase kinase 3-β (GSK3-β). Interference with these pathways, which are pivotal in determining the balance of inflammatory versus anti-inflammatory cytokines, provides a potential mechanism by which Sorafenib can modulate the macrophage cytokine phenotype. These data raise the possibility that the use of Sorafenib as cancer therapy could potentially reverse the immunosuppressive cytokine profile of tumor-associated macrophages, rendering the tumor microenvironment more conducive to an anti-tumor immune response.

Original languageEnglish (US)
Pages (from-to)1220-1228
Number of pages9
JournalInternational Immunopharmacology
Volume10
Issue number10
DOIs
StatePublished - Oct 1 2010

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Keywords

  • IL-12
  • MSK
  • Macrophages
  • P38
  • Sorafenib

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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