Premium
Upregulation of cannabinoid receptor‐1 and fibrotic activation of mouse hepatic stellate cells during Schistosoma J . infection: role of NADPH oxidase (693.13)
Author(s) -
Wang Mi,
Abais Justine,
Meng Nan,
Zhang Yang,
Ritter Joseph,
Li Pinlan,
Tang WangXian
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.693.13
Subject(s) - downregulation and upregulation , nadph oxidase , hepatic stellate cell , cannabinoid receptor , biology , schistosoma mansoni , receptor , cannabinoid , microbiology and biotechnology , chemistry , immunology , endocrinology , schistosomiasis , reactive oxygen species , gene , biochemistry , helminths , agonist
The endocannabinoid system (CS) has been implicated in schistosomiasis‐associated liver fibrosis (SSLF). However, the molecular mechanisms mediating the action of the CS in SSLF are largely unknown. The present study hypothesized that Schistosoma J. infection upregulates cannabinoid receptor (CB) signaling via activation of NADPH oxidase leading to a fibrotic phenotype in hepatic stellate cells (HSCs). A SSLF model was developed by infecting mice with Schistosoma J . cercariae in the skin. HSCs from uninfected (control) or Schistosoma J .‐infected (SSLF) mice were isolated, cultured and identified by analyzing HSC markers α‐SMA and desmin. In HSCs isolated from control or SSLF mice, both CB1 and CB2 receptors were detected, however, only the CB1 significantly increased in HSCs from SSLF mice compared to that control mice. Such increase of CB1 in HSCs was accompanied by enhanced expression of fibrotic markers α‐SMA, collagen I, and TIMP‐1. Similarly, CB1 upregulation and enhanced fibrotic changes were observed in HSCs isolated from control mice when these cells were treated with soluble egg antigen (SEA) from Schistosoma J. Interestingly, HSCs from SSLF mice or SEA‐treated HSCs from control mice exhibited enhanced superoxide (O 2 .‐ ) production as analyzed by electron spin resonance. Importantly, inhibition of O 2 .‐ production by knocking down NADPH oxidase genes (Nox1 or Nox4) prevented SEA‐induced upregulation of CB1 and fibrotic markers in HSCs. Further, CB1 gene silencing blocked SEA‐induced fibrotic changes in HSCs but had no effect on SEA‐induced O 2 .‐ production in these cells indicating a triggering role of O 2 .‐ production in CB1‐mediated fibrotic signaling. Taken together, these data suggest that the fibrotic activation of HSCs upon Schistosoma J . infection or SEA stimulation is associated with NADPH oxidase‐mediated redox regulation of CB1 expression, which may be a triggering mechanism for SSLF. Grant Funding Source : Supported by NIH grants HL057244, HL091464 and HL075316