Cutting edge: IL-4 induces suppressor of cytokine signaling-3 expression in B cells by a mechanism dependent on activation of p38 MAPK.
The signaling cascade initiated by IL-4 is classically divisible into two major pathways: one mediated by STAT6, and the other by insulin receptor substrates-1 and -2 via activation of PI3K. In murine splenic B cells, the suppressor of cytokine signaling (SOCS)3 is inducible by IL-4 via a mechanism independent of STAT6 and PI3K. SOCS3 expression increases 9-fold within 5 h of IL-4 treatment. This induction occurs normally in B cells deficient in STAT6 and is unaffected by pretreatment with the PI3K inhibitor wortmannin, or with the ERK pathway inhibitor, PD98059. However, the IL-4 induction of SOCS3 is blocked by inhibitors of either the JNK or p38 MAPK pathways (SP600125 and SB203580, respectively). Direct examination of these pathways reveals rapid, IL-4-directed activation of p38 MAPK, uncovering a previously unappreciated pathway mediating IL-4 signal transduction.
Canfield
Stephen
S
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. smc12@columbia.edu
Lee
Youngnam
Y
Schröder
Andreas
A
Rothman
Paul
P
D051698:Activating Transcription Factor 2; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D050800:STAT6 Transcription Factor; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013379:Substrate Specificity / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D050807:ets-Domain Protein Elk-1; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D015847:Interleukin-4; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases