Aldose reductase regulates doxorubicin-induced immune and inflammatory responses by activating mitochondrial biogenesis.

We have recently demonstrated that aldose reductase (AR) inhibitor; fidarestat prevents doxorubicin (Dox)-induced cardiotoxic side effects and inflammation in vitro and in vivo. However, the effect of fidarestat and its combination with Dox on immune cell activation and the immunomodulatory effects are not known. In this study, we examined the immunomodulatory effects of fidarestat in combination with Dox in vivo and in vitro. We observed that fidarestat decreased Dox-induced upregulation of CD11b in THP-1 monocytes. Fidarestat further attenuated Dox-induced upregulation of IL-6, IL-1ß, and Nos2 in murine BMDM. Fidarestat also attenuated Dox-induced activation and infiltration of multiple subsets of inflammatory immune cells identified by expression of markers CD11b+, CD11b+F4/80+, Ly6C+CCR2high, and Ly6C+CD11b+ in the mouse spleen and liver. Furthermore, significant upregulation of markers of mitochondrial biogenesis PGC-1α, COX IV, TFAM, and phosphorylation of AMPKα1 (Ser485) was observed in THP-1 cells and livers of mice treated with Dox in combination with fidarestat. Our results suggest that fidarestat by up-regulating mitochondrial biogenesis exerts protection against Dox-induced immune and inflammatory responses in vitro and in vivo, providing further evidence for developing fidarestat as a combination agent with anthracycline drugs to prevent chemotherapy-induced inflammation and toxicity.

PD-1 ligand expression by human colonic myofibroblasts/fibroblasts regulates CD4+ T-cell activity.

BACKGROUND & AIMS: A prominent role for inhibitory molecules PD-L1 and PD-L2 in peripheral tolerance has been proposed. However, the phenotype and function of PD-L-expressing cells in human gut remains unclear. Recent studies suggest that colonic myofibroblasts (CMFs) and fibroblasts are important in the switch from acute inflammation to adaptive immunity. In the normal human colon, CMFs represent a distinct population of major histocompatibility complex class II(+) cells involved in the regulation of mucosal CD4(+) T-cell responses. METHODS: PD-L1 and PD-L2 expression on human CMFs was determined using Western blot, fluorescence-activated cell sorter analysis and confocal microscopy. Lymphoproliferation assays and cytokine enzyme-linked immunosorbent assays were used to evaluate the role of B7 costimulators expressed by CMFs with regard to the regulation of preactivated T-helper cell responses. RESULTS: We demonstrate here the expression of PD-L1/2 molecules by normal human CMF and fibroblasts in situ and in culture. Both molecules support suppressive functions of CMFs in the regulation of activated CD4(+) T-helper cell proliferative responses; blocking this interaction reverses the suppressive effect of CMFs on T-cell proliferation and leads to increased production of the major T-cell growth factor, interleukin (IL)-2. PD-L1/2-mediated CMF suppressive functions are mainly due to the inhibition of IL-2 production, because supplementation of the coculture media with exogenous IL-2 led to partial recovery of activated T-cell proliferation. CONCLUSIONS: Our data suggest that stromal myofibroblasts and fibroblasts may limit T-helper cell proliferative activity in the gut and, thus, might play a prominent role in mucosal intestinal tolerance.