IL-18 Paradox in Pancreatic Carcinoma: Elevated Serum Levels of Free IL-18 are Correlated With Poor Survival

The role of the proinflammatory interleukin (IL)-18 in cancer progression remains controversial we thus examined the hypothesis that impaired antitumor immune response in pancreatic carcinoma patients is related to elevated levels of its natural inhibitor IL-18 binding protein (B: P) and, or to alteration in the IL-18 receptor complex expression and function IL-18 and IL-18 binding protein isoform a (BPa) was assessed in pancreatic carcinoma patients at various disease stages, and after surgery/chemotherapy; free bioactive IL-18 concentrations were calculated IL-18 receptor complex expression in lymphocyte Subsets was analyzed and signaling function was assessed versus healthy donors Carcinoma cells exhibited below normal IL-18BPa expression and above normal IL-18 expression. Circulating IL-18BPa and IL-18 were above controls. Unexpectedly. free unbound IL-18 serum levels were correlated with disease severity and poor survival IL-18BPa levels were unchanged by surgery but free IL-18 levels were elevated Gemcitabine with 5-fluorouracile or oxaliplitin, but not alone, increased IL-18 and free IL-18 levels statistically significantly, Without affecting IL-18BPa Spontaneous/induced IL-18 receptor alpha and receptor beta expression in peripheral blood lymphocyte subsets from patients with advanced disease were near-normal. although CD4(+) and CD8(+) cells were fewer in percentage, and fully functional in inducing interferon-gamma IL-18 is proposed as novel adjuvant cancer therapy but free IL-18 levels are increased in the blood of pancreatic circinoma patients despite elevated IL-18BP levels, and are associated with poor survival, this highlights recent experimental insights into the prometastatic and proangiogenic effects of IL-18, and suggests that careful preclinical studies are needed to determine the proper application of IL-18 in cancer therapy