Interleukin-1β enhances the production of soluble MICA in human hepatocellular carcinoma

Kohga, Keisuke; Tatsumi, Tomohide; Tsunematsu, Hinako; Aono, Satoshi; Shimizu, Satoshi; Kodama, Takahiro; Hikita, Hayato; Yamamoto, Masashi; Oze, Tsugiko; Aketa, Hiroshi; Hosui, Atsushi; Miyagi, Takuya; Ishida, Hisashi; Hiramatsu, Naoki; Kanto, Tatsuya; Hayashi, Norio; Takehara, Tetsuo
September 2012
Cancer Immunology, Immunotherapy;Sep2012, Vol. 61 Issue 9, p1425
Academic Journal
The production of soluble major histocompatibility complex class I-related chain A (MICA) is thought to antagonize NKG2D-mediated immunosurveillance. Interleukin-1β (IL-1β) is elevated in patients with chronic hepatitis C (CH), and this might contribute to the escape of hepatocellular carcinoma (HCC) cells from innate immunity. In this study, we investigated the immunoregulatory role of IL-1β in the production of soluble MICA of HCC cells. First, we investigated the correlation between the serum IL-1β levels and soluble MICA in CH patients. Serum IL-1β levels were associated with soluble MICA levels in CH patients. The serum IL-1β levels of CH patients with the HCC occurrence were significantly higher than those of CH patients without HCC. We next examined the MICA production of IL-1β-treated HCC cells. Addition of IL-1β resulted in significant increase in the production of soluble MICA in HepG2 and PLC/PRF/5 cells, human HCC cells. But soluble MICA was not detected in both non-treated and IL-1β-treated normal hepatocytes. Addition of IL-1β did not increase the expressions of membrane-bound MICA on HCC cells. These were observed similarly in various cancer cells including a gastric cancer (MKN1), two colon cancers (HCT116 and HT29) and a cervical cancer (HeLa). Addition of IL-1β also increased the expression of a disintegrin and metalloproteinase (ADAM)9 in HCC cells, and the knockdown of ADAM9 in IL-1β-treated HCC cells resulted in the decrease in the production of soluble MICA of HCC cells. These findings indicate that IL-1β might enhance the production of soluble MICA by activating ADAM9 in human HCC.


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