Interleukin-4 regulates macrophage interleukin-12 protein synthesis through a c-fos mediated mechanism.
BACKGROUND
Interleukin-4 (IL-4) treatment after lipopolysaccharide (LPS) induction inhibits macrophage (Mphi) IL-12 synthesis; however, IL-4 pretreatment (PreTx) primes the Mphi for increased LPS-induced IL-12 production. In this study we study the role of c-fos in the IL-4 priming of Mphi IL-12 synthesis.


METHODS
With a murine in vitro peritoneal M phi model, we studied the effect of either c-fos deficiency (wild type, WT; homozygous c-fos knockout, Homo KO) or c-fos overexpression to study the role of c-fos in IL-4 priming of LPS-induced M phi IL-12 synthesis.


RESULTS
(1) We first show that IL-4 PreTx results in a 72% decrease in Mphi c-fos mRNA compared with vehicle PreTx. (2) With respect to IL-12 p70 protein, IL-4 PreTx in the WT group increased LPS-induced Mphi IL-12 p70 2.2-fold compared with vehicle PreTx. Compared with vehicle PreTx in the WT group, vehicle PreTx in the Homo KO group followed by LPS stimulation resulted in a 2.8-fold increase in IL-12 p70 in the Homo KO group. IL-4 PreTx did not significantly increase IL-12 p70 over vehicle PreTx in the Homo KO group. (3) We studied the effect of c-fos overexpression on LPS-induced Mphi IL-12 production when primed with IL-4. Overexpression of c-fos completely inhibited IL-4 primed LPS-induced IL-12 p70 protein synthesis.


CONCLUSIONS
These data demonstrated that down-regulation of c-fos is an integral part of the IL-4 priming process for Mphi IL-12 production.
Roy
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Departments of Surgery, Pharmacology, and Anesthesiology, University of Minnesota, Minneapolis Veterans Affairs Medical Center, 55417, USA.
Charboneau
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Melnyk
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Barke
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D000818:Animals; D002478:Cells, Cultured; D016762:Genes, fos; D006720:Homozygote; D018664:Interleukin-12 / Q000235:genetics*; D015847:Interleukin-4 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D016760:Proto-Oncogene Proteins c-fos / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014162:Transfection
D008070:Lipopolysaccharides; D016760:Proto-Oncogene Proteins c-fos; D011994:Recombinant Proteins; D018664:Interleukin-12; D015847:Interleukin-4