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STAT4 Isoforms Differentially Regulate Th1 Cytokine Production and the Severity of Inflammatory Bowel Disease¹

John T. O'Malley^*, Rajaraman D. Eri, Gretta L. Stritesky^*, Anubhav N. Mathur^*, Hua-Chen Chang^*, Harm HogenEsch, Mythily Srinivasan and Mark H. Kaplan^2,*

^* Department of Pediatrics, HB Wells Center for Pediatric Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Oral Pathology, Medicine and Radiology, School of Dentistry, Indiana University Purdue University IN 46205; and Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907

STAT4, a critical regulator of inflammation in vivo, can be expressed as two alternative splice forms, a full-length STAT4, and a STAT4β 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 STAT4 or STAT4β isoform into SCID mice, we determined that although both isoforms mediate inflammation and weight loss, STAT4β promotes greater colonic inflammation and tissue destruction. This correlates with STAT4 isoform-dependent expression of TNF- and GM-CSF in vitro and in vivo, but not Th1 expression of IFN- or Th17 expression of IL-17, which were similar in STAT4- and STAT4β-expressing T cells. Thus, higher expression of a subset of inflammatory cytokines from STAT4β-expressing T cells correlates with the ability of STAT4β-expressing T cells to mediate more severe inflammatory disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by U.S. Public Health Service Award AI45515 and AI57459 (to M.H.K.) from the National Institutes of Health. J.T.O. and G.L.S. were supported by a Training Grant in Immunology and Infectious Disease (T32AI060519).

² Address correspondence and reprint requests to Dr. Mark H. Kaplan, Department of Pediatrics, Herman B. Wells Center for Pediatric Research, 702 Barnhill Drive, RI 2600, Indiana University School of Medicine, Indianapolis, IN 46202. E-mail address: mkaplan2{at}iupui.edu

³ Abbreviations used in this paper: IBD, inflammatory bowel disease; WT, wild type; MLN, mesenteric lymph node; pSTAT4, phospho-STAT4.

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