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1 Department of Medicine and Nephrology, Johns Hopkins Univeristy School of Medicine, Baltimore, MD, USA
2 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: hrabb1{at}jhmi.edu.
Recent data supports a modulatory role for CD4 T cells in experimental renal ischemia-reperfusion injury (IRI). CD4 T cells can functionally differentiate to either a Th1 (IFN-
. producing) or the counterbalancing Th2 (IL-4) phenotype. The enzymes Signal Transducers and Activators of Transcription (STAT) 4 and STAT6 regulate Th1 or Th2 differentiation and cytokine production respectively. We therefore hypothesized that mice that were STAT4 deficient would be protected from renal IRI, and that STAT6 deficient mice would have a more severe course. Intracellular cytokine staining of splenocytes from STAT4-/- or STAT6-/- exhibited distinct IFN- and IL-4 cytokine expression profiles. STAT6-/- had markedly worse renal function and tubular injury postischemia compared to wild type. STAT4-/- had only mildly improved function. Renal phagocyte infiltration and ICAM-1 upregulation were similar in STAT4-/-, STAT6-/- and wild type. To evaluate if the mechanism of the marked worsening in the STAT6-/- mice could be due to IL-4 deficiency, IL-4 deficient mice were studied, and had similar postischemic phenotype to STAT6-/- mice. These data demonstrate that the STAT6 pathway has a major protective role in renal IRI. IL-4 deficiency is a likely mechanism underlying the STAT6 effect. A "yin-yang" role for inflammation is emerging in renal IRI, similar to recent observations in atherosclerosis.
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