Characterization of the CD40L/Oncostatin M/Oncostatin M receptor axis as an antiviral and immunostimulatory system disrupted in chronic HCV infection

Abstract

Background & aims: Oncostatin M (OSM) is an inflammatory cytokine which interacts with a heterodimeric receptor formed by gp130 and either OSMRβ or LIFR. Here we have analysed OSM and its receptors in livers with chronic hepatitis C (CHC) and studied the factors that regulate this system.

Methods: OSM, OSM receptors and OSM-target molecules were studied by immunohistochemistry and/or qPCR analysis in livers from CHC patients and controls. We determined the production of OSM by CD40L-stimulated antigen presenting cells (APC) and its biological effects on HuH7 cells containing HCV replicon (HuH7 Core-3').

Results: OSM was upregulated in livers with CHC and its production was mapped to CD11c+ cells. OSM levels correlated directly with inflammatory activity and CD40L expression. In vitro studies showed that OSM is released by APC upon interaction with activated CD4+ T cells in a CD40L-dependent manner. Culture of HuH7 Core-3' cells with supernatant from CD40L-stimulated APC repressed HCV replication and induced IL-7 and IL-15Rα. These effects were dampened by antibodies blocking OSM or gp130 and by silencing OSMRβ. In CHC livers OSMRβ and LIFR were significantly downregulated and their values correlated with those of OSM-induced molecules. Experiments in HuH7 cells showed that impaired STAT3 signaling and exposure to TGFβ1, two findings in CHC, are factors involved in repressing OSMRβ and LIFR, respectively.

Conclusions: OSM is a cytokine possessing vigorous antiviral and immunostimulatory properties which is released by APC upon interaction with CD40L present on activated CD4+ T cells. In livers with CHC, OSM is overexpressed but its biological activity appears to be hampered because of downregulation of its receptor subunits.

Keywords: APC; CD40 ligand; CD40L; CHC; CLC; DCs; HCV; IFN; LIFR; LPS; MoDCs; OSM; OSM receptor beta subunit; OSMRβ; PBMC; PGN; Poly I:C; RT-PCR; SVR; TLR; antigen presenting cells; cardiotrophin-like-cytokine; chronic hepatitis C; dendritic cells; hepatitis C virus; interferon; leukemia inhibitory factor receptor; lipopolysaccharide; monocyte-derived-DCs; oncostatin M; peptidoglycan; peripheral mononuclear cells; polyinosinic:polycytidylic acid; qPCR; quantitative real time PCR; reverse transcription polymerase chain reaction; sustained virological response; toll-like receptors.