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 STAT4 alpha, and a STAT4 beta 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 alpha or STAT4 beta isoform into SCID mice, we determined that although both isoforms mediate inflammation and weight loss, STAT4 beta 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 STAT4 alpha- and STAT4 beta-expressing T cells. Thus, higher expression of a subset of inflammatory cytokines from STAT4 beta-expressing T cells correlates with the ability of STAT4 beta-expressing T cells to mediate more severe inflammatory disease.