Overexpression of KLF14 protects against immune-mediated hepatic injury in mice

Abstract

The underlying immunopathogenic mechanisms of autoimmune hepatitis (AIH) have not yet been well elucidated. An impairment in regulatory T cells (Tregs) is key to the development of AIH. Krüppel-like factors (KLFs) regulate a broad of cellular processes including immunocyte maturation. KLF14 may regulate Treg differentiation, but the biological functions remain far from elucidated. In this study, we identified the hepatic expression of KLF14 in human and murine liver diseases. Immune-mediated hepatitis was induced by concanavalin A (Con A). A KLF14 recombinant adenoviruses plasmid (Ad-KLF14) was constructed and injected into mice. Tregs were assessed by flow cytometry analysis; inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), were tested by enzyme-linked immunosorbent assay (ELISA). The expression of KLF14 was suppressed in a time-and dose-dependent manner. Changes in cytokine levels were consistent with the degree of hepatic injury. Overexpression of KLF14 protected the liver from immune-mediated damage in vivo. Ad-KLF14 transfection before Con A challenge increased the frequency of Tregs in liver mononuclear cells (MNCs), and suppressed the expression of cytokines. All of these improvements were completely abrogated after Treg deletion in vivo by intraperitoneal injection of a CD25 antibody. In conclusion, these data suggest that KLF14 plays an asyet unrecognized role in immune-mediated hepatitis mainly via induced Treg differentiation. Our findings extend the knowledge of the biological function of KLF14 to the autoimmune disease field, and indicate the possibility of KLF14 as a therapeutic target in AIH patients.

The role of KLF14 in multiple disease processes

“…17 However, another study yielded conflicting findings as to the role of KLF14 in Con A-induced mice hepatitis. 3 The study found that the expression level of KLF14 was decreased in AIH patients and experimental AIH mice models as compared to normal controls. KLF14 overexpression did not induce any significant change in Tregs, but the frequency of Tregs was increased after the mice transfected with the plasmid were challenged with Con A.…”

“…These data suggested that KLF14‐induced differentiation of Treg was closely related to autoimmune inflammation in mice colitis . However, another study yielded conflicting findings as to the role of KLF14 in Con A‐induced mice hepatitis . The study found that the expression level of KLF14 was decreased in AIH patients and experimental AIH mice models as compared to normal controls.…”

“…Multiple studies have indicated that KLFs are involved in the many different physiological and pathological processes. In recent studies, KFLs have been reported to play a critical role in the maintenance of homeostasis of many critical systems, including cardiovascular, cerebral, renal, immune, digestive, respiratory, and hematopoietic system . For example, in hepatobiliary system, KLF2 and KLF11 are shown to play roles in the hepatic fibrogenesis.…”

“…In recent studies, KFLs have been reported to play a critical role in the maintenance of homeostasis of many critical systems, including cardiovascular, cerebral, renal, immune, digestive, respiratory, and hematopoietic system. [2][3][4][5][6][7][8] For example, in hepatobiliary system, KLF2 and KLF11 are shown to play roles in the hepatic fibrogenesis. KLF4, KLF6, KLF8, KLF9, and KLF17 are shown to be involved in the pathogenesis of hepatocellular carcinoma (HCC) by modulating the invasion, proliferation, apoptosis, and migration of the cancer cells.…”

The JAK inhibitor tofacitinib ameliorates immune‑mediated liver injury in mice

“…The resuspended cells were processed with 30% Percoll (Sigma-Aldrich; Merck KGaA) and gently overlaid onto 70% Percoll. After density gradient centrifugation at 1,000 × g for 30 min, liver MNCs were harvested from the interface of the Percoll gradient (37). The MNCs collected were used for further fluorescence-activated cell sorting (FACS) analysis.…”