Interleukin-1β enhances the production of soluble MICA in human hepatocellular carcinoma.
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.
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Keisuke
K
Kohga
Tomohide
T
Tatsumi
Hinako
H
Tsunematsu
Satoshi
S
Aono
Satoshi
S
Shimizu
Takahiro
T
Kodama
Hayato
H
Hikita
Masashi
M
Yamamoto
Tsugiko
T
Oze
Hiroshi
H
Aketa
Atsushi
A
Hosui
Takuya
T
Miyagi
Hisashi
H
Ishida
Naoki
N
Hiramatsu
Tatsuya
T
Kanto
Norio
N
Hayashi
Tetsuo
T
Takehara
D051722:ADAM Proteins / Q000096:biosynthesis / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D053583:Interleukin-1beta / Q000097:blood / Q000276:immunology* / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology; D008113:Liver Neoplasms / Q000097:blood / Q000276:immunology* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000276:immunology; D008875:Middle Aged
D015395:Histocompatibility Antigens Class I; D053583:Interleukin-1beta; C099187:MHC class I-related chain A; D008565:Membrane Proteins; D051722:ADAM Proteins; C098339:ADAM9 protein, human