Immunoregulatory effects of Indoleamine 2,3-dioxygenase in Primary Biliary Cirrhosis & Hepatitis C Virus-induced Liver Cirrhosis

Abstract

Indoleamine 2, 3-dioxygenase (IDO) is an enzyme which is involved in the degradation of L-tryptophan through kynurennine pathway. IDO induced immunosupression can be clinically beneficial for autoimmune diseases. Primary biliary cirrhosis is well defined by autoimmune lesion of intrahepatic bile duct epithelial cells. There is evidence that impaired IDO level contributes to the development of autoimmunity in PBC. Our aim was to assess the expression of IDO in our cell culture model and in PBC patients. Tryptophan metabolites are available and could potentially demonstrate utility in PBC. The current study establishes, for the first time, the expression of IDO in the H69 cell line and increase rate of conversion of tryptophan to kynurenine in patients with PBC. Furthermore, clinical biopsies from PBC patients demonstrated that the expression of IDO was observed not only in cholangiocytes as described earlier but also in hepatocytes. In the presence of TGF-β impaired IDO activity might contribute in the progression of disease scenario. The use of tryptophan metabolites could enhance the effects of IDO and compensate for the lack of efficiency of existing immunotherapeutic strategies. The positive effect of tryptophan metabolites on Human CD4+ T cells to induce polarization toward T-reg phenotype may render a prospective means to ameliorate the consequence of immunotherapy for the management of PBC. In this study we analyzed that the immunomodulatory enzyme IDO activity providing new insight into the pathogenesis of PBC. IDO-mediated immunosupression through tryptophan metabolites may be used against the progression of PBC. Hepatitis C virus (HCV) has infected more than 12 million Pakistani people. Our aim was to assess the expression and enzymatic activity of IDO in HCV patients. We observed high expression of IDO in HCV induced liver cirrhotic patients. IDO was significantly higher in the serum samples of HCV infected patients as compare to the control. It suggest that IDO may involved in the immunosuppression and possibly contribute to progression of HCV infection. Our findings advocated that the HCV patients with over expression of IDO might have poor prognosis, and IDO may become a newly useful marker for HCV induced liver cirrhosis. Thus, blocking IDO might provide new strategies as an adjuvant therapy intervention for HCV. The modeling of the biological regulatory networks (BRNs) using of Rene Thomas Formalism, we observed the critical role of TGF-β and IFN-γ in the suppression and induction of IDO. We observe two types of steady states behaviors in the state graph. The cycle shows the homeostasis of IDO and TGF-β while IFN-γ is inactive (silent). The stable state shows the high expression levels of IFN-γ and IDO while TGF-β is silent. There is a divergence from the cycle towards the stable states and it is observed that this divergence occurs when IFN-γ has expression levels. In cancers condition if we induce TGF-β which is negative regulator of IDO can create the homeostasis. Otherwise the expression of IDO can be inhibited by 1-MT. In case of autoimmune diseases if we inhibit the TGF-β the induction of IDO may produce homeostasis. Tryptophan downstream metabolites can also beneficial in this regard. Key words: IDO, PBC, HCV, IFN-γ, TGF-β, 1-MT, H69, Tryptophan metabolites, BRNs