1). Depending on the initial site of activation, Obeticholic Acid apoptosis can be initiated through an extrinsic

or intrinsic pathway.1 Most prominent among the cytokines that can induce apoptosis of hepatocytes are the members of the TNF receptor superfamily, CD95 (Apo1/Fas), tumor necrosis factor alpha (TNF, CD120), and TNF-related apoptosis inducing ligand (TRAIL). These cytokines exert physiological functions through their cognate receptors, namely the CD95 receptor (Apo1/Fas receptor), TNF receptor type 1 (TNF-R1, p55/65, CD120a) and type 2 (TNF-R2, p75/80, CD120b), TRAIL receptor type 1 and type 2. The role of this cytokine family in hepatocarcinogenesis varies according to the subsequent intracellular signaling events (see Table 1). Failure of transformed cells to undergo apoptosis severely disrupts tissue homeostasis and allows proliferation of the resistant clone, a phenomenon that is frequently observed in HCC, and such failure correlates with decreased expression of the CD95 receptor.2,3 In addition to downregulation of apoptosis receptors in HCC, increased SCH727965 expression and secretion of the CD95-ligand has been found.4 Thus the threshold to undergo apoptosis in transformed cells is increased and the malignant tissue is capable of inducing apoptosis in lymphocytes that are directed against HCC cells, thereby evading a potential immunological

control mechanism. Decreased sensitivity towards the CD95 signaling pathway is closely related to the malignant phenotype of HCC and has been linked to a poor response to treatment with cytotoxic drugs, as well as the clinical outcome following resection.4–6 In contrast to the CD95 signaling pathway, TNF is a pleiotropic cytokine involved not only in apoptosis, but also with inflammation, hepatocyte protection and proliferation. Although TNF was initially identified as a factor

that induces cell death in sarcoma, and polymorphisms of the TNF gene have been linked to the emergence of HCC, the role of TNF in hepatocarcinogenesis not clearly defined.7–9 The response of a cell towards TNF signaling is determined by the transcription 上海皓元医药股份有限公司 factor NF-κB. If NF-κB is activated, hepatocyte survival and proliferation commences. Conversely, cells undergo apoptosis when NF-κB is transcriptionally inactive (see below). The proinflammatory cytokines lymphotoxin alpha (LTα) and beta (LTβ) activate the TNF receptor as well as the membrane bound LTβ receptor (LTβR). In this way, they contribute to the activation of NF-κB through both the canonical and non-canonical pathway. Physiologically, LTα and LTβ are expressed on activated lymphocytes and NK T-cell types, especially in response to viral hepatitis. Recently, it was shown that these receptors can be induced in hepatocytes and promote the development of HCC in viral hepatitis or when overexpressed in mice.