Activins and Follistatin in Chronic Hepatitis C and Its Treatment with Pegylated‐Interferon‐α Based Therapy

Abstract

Pegylated-interferon-α based therapy for the treatment of chronic hepatitis C (CHC) is considered suboptimal as not all patients respond to the treatment and it is associated with several side effects that could lead to dose reduction and/or termination of therapy. The currently used markers to monitor the response to treatment are based on viral kinetics and their performance in the prediction of treatment outcome is moderate and does not combine accuracy and their values have several limitations. Hence, the development of new sensitive and specific predictor markers could provide a useful tool for the clinicians and healthcare providers, especially in the new era of interferon-free therapy, for the classification of patients according to their response to the standard therapy and only subscribing the novel directly acting antiviral drugs to those who are anticipated not to respond to the conventional therapy and/or have absolute contraindications for its use. The importance of activins and follistatin in the regulation of immune system, liver biology, and pathology has recently emerged. This review appraises the up-to-date knowledge regarding the role of activins and follistatin in liver biology and immune system and their role in the pathophysiology of CHC.

Activins and their related proteins in colon carcinogenesis: insights from early and advanced azoxymethane rat models of colon cancer

“…Activins play crucial roles in many cellular homeostatic functions including cell proliferation and differentiation, wound repair and regulation of immune responses [10]. Pathological increase in activin βA-subunit protein and mRNA has been observed in malignant tissues obtained from patients with CRC and the expression was stage-dependent [19–21].…”

“…In this regards, gene deletion of activin βA- and βB-subunits resulted in completely different phenotypes and the insertion of INHBB in INHBA −/− mice partially restored the lost functions [44, 45]. Additionally, there is a tremendous gap in our knowledge and understanding of the potential physiological and pathological roles of the other activin isoforms (B & AB) in the different cells and tissues since the majority of studies were mainly conducted on activin-A only [10]. Nevertheless, a recent study has shown that patients with breast cancer and were positive for epidermal growth factor receptor 2/neu, which is a marker of carcinogenesis, had significantly lower serum concentrations of activin-AB [51].…”

“…Among these pathways, the members of transforming growth factor (TGF)-β family have recently been suggested as potential stage-dependent targets for the treatment of CRC and/or prevention of resistance associated with chemotherapy [9]. Activins belong to the TGF-β family and the mature activins consist of hetero- or homodimers of 2 β-subunits (βA and βB) resulting in three distinct proteins named activin-A (βA-βA), activin-B (βB-βB) and activin-AB (βA-βB) [10]. The canonical pathway for activins, following the activation of their type II receptors (ACTRIIA & ACTRIIB), shares the same intracellular mediators with TGF-β and both are dependent on smad2, 3 and 4 [11].…”

Downregulation of activin‑signaling gene expression in passaged normal human dermal fibroblasts

“…Activin A and follistatin are produced by normal and abnormal hepatocytes and help regulate hepatocyte regeneration in the healthy liver. Pathological increase of both activin and follistatin in hepatocyte is shown with several liver diseases including fibrosis, cirrhosis, and hepatocellular carcinoma (16). Activin A has shown an increase in serum from older women (43-47 years old) relative to younger women (19-38 years old) (17,18).…”

Activin Biology After Lung Transplantation

“…High activin to follistatin ratio therefore favors a proinflammatory fibrotic state. 3 Activin A and its antagonist follistatin have been recognized as regulatory factors in a number of acute and chronic diseases including cirrhosis, 6 rheumatoid arthritis, 7 chronic kidney disease, 8 cachexia, 9 and several lung diseases. 10-14 …”