Cytokinome Profile of Patients with Type 2 Diabetes and/or Chronic Hepatitis C Infection

Abstract

Both type 2 diabetes (T2D) and chronic hepatitis C (CHC) infection are associated with increased risk of developing hepatocellular carcinoma (HCC). Cytokines are known to play an important role not only in the mechanisms of insulin resistance and glucose disposal defects but also in the pathological processes occurring in the liver during viral infection. We evaluated the serum levels of many cytokines, chemokines, adipokines and growth factors in patients with type 2 diabetes, CHC, CHC-related cirrhosis, CHC and type 2 diabetes and CHC-related cirrhosis and type 2 diabetes by BioPlex assay. The obtained data evidenced that the serum levels of some proteins are significantly up-regulated in all the patients or in those with only one disease and are often higher, even if in different amounts, when both diseases are associated. In particular, our results can be useful for the clinical monitoring of patients because they give specific information in regard to the progression from CHC to LC and CHD to LCD. Moreover, some molecules have shown significant correlations with clinical/biochemical data, suggesting the possibility to define mini-panels that can be used as specific markers for the different disease staging. However, our observations demonstrate that an integrated approach is much more powerful than isolated measurements to evaluate specific stages of these two complex pathologies (type 2 diabetes and chronic CHC hepatitis) alone or when they are concomitant in a patient. In fact it has emerged as an accurate, simple, specific, noninvasive, reproducible and less expensive method that, in future, could be included in routine clinical practice to monitor the association of type 2 diabetes and/or CHC to liver cirrhosis and, possibly, to cancer, and to improve the prognosis of these diseases.

The role of chemokines in acute and chronic hepatitis C infection

“…57 These ligands may also be induced by IL-12 and IL-18 production and may depend on IL-6 amplifier activity for efficient gene expression. [58][59][60][61][62][63] Moreover, IFN-c, TNF-a and IL-1b are capable of stimulating CXCL2 and CCL2 expression in vitro.…”

“…58 By evaluating a panel of cytokines, chemokines and growth factors in patient serum, they identified a profile of pro-inflammatory cytokines that were upregulated in HCC and correlated with b-NGF, thus gaining a greater understanding of the link between cancer and inflammation. Constantini et al 60 also adopted a systems approach to discriminate between isolated cases of chronic hepatitis C infection and HCV infection with associated hepatic disease or T2D. They found that CXCL1 and CXCL9 were consistently upregulated in chronic HCV infection and associated liver disease with or without T2D as a disease modifier.…”

“…143,155,157 Both mRNA and protein content of CCL5 are significantly increased in patients with high histological activity index and serum alanine aminotransferase, and its expression correlates positively with disease severity. 60 Stimulation of activated HSCs with either TNF-a or IL-1b potently induces CCL5 production through an NF-kb-dependent mechanism. 158 Autocrine CCL5 is then thought to induce downstream phosphorylation of ERK and focal adhesion kinase in HSCs with ensuing increases in HSC proliferation and migration.…”

“…175,176 Moreover, extrahepatic disease is believed to complicate prognosis and further increase the risk of developing HCC and type II diabetes (T2D). 60 HCV-EHDs are characterized by sustained Th1 responses, the potencies of which correlate with disease severity. 175,176 A signature Th1 cytokine profile has been implicated in the induction of HCV-related autoimmune disease and the observed ability of HCV to infect islet cells and thyrocytes in vitro has raised the hypothesis that Th1 responses in the infected liver are analogous to those mediating autoimmune and systemic HCV-EHDs.…”

Gene expression signature of human HepG2 cell line

“…In fact, the presence of virosis and/or diabetes covers or mimics the molecular signals specific for the cancer evolution, making it difficult to discriminate between changes due to the progression of the viral disease or, worse, to the concomitant progression of virosis and diabetes, from the signaling specifically related to the progression of the cancerous disease. In recent years, our group is learning how to discriminate among the numerous signals delivered by cytokines, specifically those which can be attributed specifically to the development of cancer in the presence of HCV or HCV and diabetes (Capone et al, 2010;Costantini et al, 2010Costantini et al, , 2012. For this purpose we used the technique of multiplexing that allows us to measure quickly and efficiently simultaneous variations of a very large number of cytokines (up to about 50 different cytokines), to highlight specific molecular panels able to discriminate and describe the different stages of this cancer.…”