| The multikinase inhibitor sorafenib reverses the suppression of IL-12 and enhancement of IL-10 by PGE₂ in murine macrophages. | |
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MedLine Citation:
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PMID: 20637838 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Justin P Edwards; Leisha A Emens |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-07-15 |
Journal Detail:
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Title: International immunopharmacology Volume: 10 ISSN: 1878-1705 ISO Abbreviation: Int. Immunopharmacol. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-04 Completed Date: 2011-02-15 Revised Date: 2012-05-07 |
Medline Journal Info:
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Nlm Unique ID: 100965259 Medline TA: Int Immunopharmacol Country: Netherlands |
Other Details:
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Languages: eng Pagination: 1220-8 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier B.V. All rights reserved. |
Affiliation:
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Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Benzenesulfonates / pharmacology* Cell Line Dinoprostone / metabolism* Glycogen Synthase Kinase 3 / antagonists & inhibitors, metabolism Interleukin-10 / genetics, metabolism* Interleukin-12 / genetics, metabolism* Macrophages / drug effects*, metabolism* Mice Protein Kinase Inhibitors / pharmacology Proto-Oncogene Proteins c-akt / antagonists & inhibitors, metabolism Pyridines / pharmacology* STAT3 Transcription Factor / genetics, metabolism Suppressor of Cytokine Signaling Proteins / genetics, metabolism Toll-Like Receptors / antagonists & inhibitors, metabolism p38 Mitogen-Activated Protein Kinases / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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P50 CA88843/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Benzenesulfonates; 0/Protein Kinase Inhibitors; 0/Pyridines; 0/STAT3 Transcription Factor; 0/Socs3 protein, mouse; 0/Stat3 protein, mouse; 0/Suppressor of Cytokine Signaling Proteins; 0/Toll-Like Receptors; 0/sorafenib; 130068-27-8/Interleukin-10; 187348-17-0/Interleukin-12; 363-24-6/Dinoprostone; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 2.7.11.26/Glycogen Synthase Kinase 3 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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