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PMID: 12213961 Published · ppublish English Journal Article

STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 99 ·No. 19 ·2002-09-17 ·Pages 12281-6

Morinobu A, Gadina M, Strober W, Visconti R, Fornace A, Montagna C, Feldman GM, Nishikomori R, O'Shea JJ

Abstract

T helper 1 (T(H)1) differentiation and IFN-gamma production are crucial in cell-mediated immune responses. IL-12 is an important regulator of this process and mediates its effects through signal transducer and activator of transcription 4 (STAT4). IFN-gamma production is also regulated by the p38 mitogen-activated kinase pathway, although the mechanisms are ill-defined. We show here that GADD45-beta and GADD45-gamma can induce STAT4 S721 phosphorylation via the MKK6/p38 pathway. Thus, STAT4 could be a target that accounts for the defects in cell-mediated immunity associated with perturbations in the p38 pathway. To investigate the biological significance of STAT4 S721 phosphorylation, we reconstituted primary spleen cells from STAT4-deficient mice with wild-type and mutated STAT4, by using a retroviral gene transduction. We demonstrated that expression of wild-type STAT4, but not the S721A mutant, restored normal T(H)1 differentiation and IFN-gamma synthesis. The inability of STAT4 S721 to restore IFN-gamma production was not caused by decreased IL-12R expression because the STAT4 S721 mutant also failed to restore IFN-gamma production in STAT4-deficient IL-12Rbeta2 transgenic cells. Importantly, STAT4 S721A-transduced cells showed normal proliferative response to IL-12, illustrating that serine phosphorylation is not required for IL-12-induced proliferation. Additionally, the results imply the existence of STAT4 serine phosphorylation-dependent and -independent target genes. We conclude that phosphorylation of STAT4 on both tyrosine and serine residues is important in promoting normal T(H)1 differentiation and IFN-gamma secretion.

MeSH Terms
Animals Calcium-Calmodulin-Dependent Protein Kinases/metabolism Cell Division/physiology Cells, Cultured DNA-Binding Proteins/chemistry,deficiency,genetics,metabolism Interferon-gamma/biosynthesis Interleukin-12/metabolism,pharmacology Intracellular Signaling Peptides and Proteins MAP Kinase Kinase 6 Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Mitogen-Activated Protein Kinases/metabolism Mutagenesis, Site-Directed Phosphorylation Proteins/metabolism Receptors, Interleukin/deficiency,genetics,metabolism Receptors, Interleukin-12 Recombinant Proteins/chemistry,genetics,metabolism STAT4 Transcription Factor Serine/chemistry Signal Transduction Th1 Cells/drug effects,immunology,metabolism Trans-Activators/chemistry,deficiency,genetics,metabolism Tyrosine/chemistry p38 Mitogen-Activated Protein Kinases
Chemicals
DNA-Binding Proteins GADD45 protein Intracellular Signaling Peptides and Proteins Proteins Receptors, Interleukin Receptors, Interleukin-12 Recombinant Proteins STAT4 Transcription Factor Stat4 protein, mouse Trans-Activators Interleukin-12 Tyrosine Serine Interferon-gamma Calcium-Calmodulin-Dependent Protein Kinases Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases MAP Kinase Kinase 6 Map2k6 protein, mouse
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Morinobu Akio
Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA. morinoba@mail.nih.gov
Gadina Massimo
Strober Warren
Visconti Roberta
Fornace Albert
Montagna Cristina
Feldman Gerald M
Nishikomori Ryuta
O'Shea John J
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.182618999
Email
morinoba@mail.nih.gov
Published
2002-09-17
Epub
2002-00-04
Pages
12281-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC129436
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.182618999 PMC Full Text View journal details
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