STAT4 isoforms differentially regulate Th1 cytokine production and the severity of inflammatory bowel disease.
STAT4, a critical regulator of inflammation in vivo, can be expressed as two alternative splice forms, a full-length STAT4alpha, and a STAT4beta isoform lacking a C-terminal transactivation domain. Each isoform is sufficient to program Th1 development through both common and distinct subsets of target genes. However, the ability of these isoforms to mediate inflammation in vivo has not been examined. Using a model of colitis that develops following transfer of CD4(+) CD45RB(high) T cells expressing either the STAT4alpha or STAT4beta isoform into SCID mice, we determined that although both isoforms mediate inflammation and weight loss, STAT4beta promotes greater colonic inflammation and tissue destruction. This correlates with STAT4 isoform-dependent expression of TNF-alpha and GM-CSF in vitro and in vivo, but not Th1 expression of IFN-gamma or Th17 expression of IL-17, which were similar in STAT4alpha- and STAT4beta-expressing T cells. Thus, higher expression of a subset of inflammatory cytokines from STAT4beta-expressing T cells correlates with the ability of STAT4beta-expressing T cells to mediate more severe inflammatory disease.
O'Malley
John T
JT
Department of Pediatrics, HB Wells Center for Pediatric Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Eri
Rajaraman D
RD
Stritesky
Gretta L
GL
Mathur
Anubhav N
AN
Chang
Hua-Chen
HC
Hogenesch
Harm
H
Srinivasan
Mythily
M
Kaplan
Mark H
MH
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D017710:Lymphocyte Transfusion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D050797:STAT4 Transcription Factor / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017384:Sequence Deletion; D012720:Severity of Illness Index; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D015431:Weight Loss / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D018836:Inflammation Mediators; D020033:Protein Isoforms; D011948:Receptors, Antigen, T-Cell; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D014409:Tumor Necrosis Factor-alpha
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