Role of Jak3 in hepatic inflammation during ulcerative colitis
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BackgroundJanus kinase 3 (Jak3) is a nonreceptor protein kinase that plays essential role in hematopoietic and intestinal epithelial differentiation. Previously, we reported that loss of Jak3 exacerbates symptoms in murine model of DSSinduced colitis through compromised intestinal differentiation of goblet cells. Studies suggest a linkage between colitis and hepatic steatosis, but the genetic regulation of such a regulation and the role of Jak3 in hepatic steatosis is not known. In this work, we investigated the tissuespecific role of Jak3 in maintaining hepatic homeostasis during intestinal inflammation.MethodsWe used a global Jak3 KO (Jak3/) mice and their littermate control wild type mice in a model of DSSinduced colitis and compared the effects of Jak3 on hepatic steatosis and the status of hepatic TLR signaling and TGFb1 pathways. We also investigated the tissue specific roles of Jak3 in liver steatosis during DSSinduced colitis using organs collected at the end of the study and analyzed using a combination of flow cytometry, confocal microscopy, and western analysis techniques.ResultsOur results show increased severity towards DSSinduced colitis in Jak3/ mice, IECJak3/ and IMMJak3/compared to their littermates controls. The inflammations in Jak3/ or IECJak3/ and IMMJak3/mice showed increased disease activity scores that were associated with shortening of colon length, reduced cecum length, decreased crypt heights, increased liver to body weight ratio, and increased hepatic steatosis compared to their littermate controls. To determine the tissue specific role of Jak3, our data show a highdegree of association between ulcerative colitis and hepatic inflammation in all three Jak3KO groups indicating an essential role of Jak3 in maintaining tissue homeostasis and immunotolerance. IHC studies indicated a role of Kupffer cells in hepatic inflammation. A differential flowcytometric assay showed an increased influx of monocytes, but reduced differentiation of residential Kupffer cells in Jak3 KO mice compared to control. Moreover, KO mice showed an increased hepatic expression of TLR2 and TLR4 and a higher IL6, IL17 and Tnf as compared to the control mice. Genetic analysis showed, either intestinal inflammation by DSS or loss of Jak3 without DSS both resulted in increased expression of TGFb1, Fn1, and decreased expression of Cola1 and aSMA. Together, these results showed that loss of Jak3 expression leads to compromise tolerance of Kupffer cells coupled with increased extravasation of the circulating monocytes into the liver. This could lead to exacerbation of hepatic inflammation in ulcerative colitis. In addition, we also found an increased Th17 effector function and simultaneous suppression of Treg cell proliferation in the absence of Jak3, when compared to its control mice.ConclusionCollectively, these results indicate that Jak3 plays a major role in regulating the hepatic inflammation during ulcerative colitis.
