{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:45:19Z","timestamp":1791276319180,"version":"4.1.0"},"reference-count":26,"publisher":"BMJ","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gut"],"accepted":{"date-parts":[[2010,5,28]]},"published-print":{"date-parts":[[2011,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background and aims<\/jats:title>\n                    <jats:p>\n                      Interactions between hepatic stellate cells (HSCs) and immune cell subsets have emerged as important determinants of liver fibrosis progression and regression. Natural killer (NK) cells have an antifibrotic activity through killing of activated HSCs. In liver injury NK cell expression of activating\/inhibitory killer immunoglobulin-related receptors (aKIR\/iKIR) and their ratio are significantly increased, while class I major histocompatibilty (MHC) expression by activated HSCs is decreased. The aim of this study was to amplify the antifibrotic activity of NK cells and ameliorate hepatic fibrosis by\n                      <jats:italic>iKIR<\/jats:italic>\n                      silencing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Human lymphocytes from patients with hepatitis C virus (HCV) infection were transfected with specific\n                      <jats:italic>iKIR<\/jats:italic>\n                      small interfering RNAs (siRNAs) or non-silencing control siRNAs, then co-cultured with a human HSC line and assessed for fibrogenic activity. To induce hepatic fibrosis, carbon tetrachloride was administrated to BALBc SCID-Beige male mice (lacking B\/T\/NK cells) for 4\u2005weeks. Splenocytes from naive SCID donors (lacking B\/T cells but with preserved NK cells) were transfected in vitro with either\n                      <jats:italic>iKIR<\/jats:italic>\n                      siRNA or non-silencing control siRNA, and then were transferred to the fibrotic SCID-Beige recipients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Transfection with\n                      <jats:italic>iKIR<\/jats:italic>\n                      or positive control siRNAs (mice and human) decreased mRNA expression of\n                      <jats:italic>iKIR<\/jats:italic>\n                      and mitogen-acivated protein kinase 1 (MAPK1). Consequently, total NK cells and NK cell degranulation were increased (p=0.01), consistent with NK cell stimulation. Compared with healthy lymphocytes, when HCV lymphocytes were transfected with non-silencing control siRNA and co-cultured with HSCs there was increased \u03b1-smooth muscle actin (\u03b1SMA) expression, reflecting HSC activation. Expression of \u03b1SMA in co-cultures was attenuated when HCV lymphocytes were transfected with\n                      <jats:italic>iKIR<\/jats:italic>\n                      siRNA. In SCID-Beige recipients, hepatic fibrosis and serum alanine aminotransferase (ALT) levels were significantly attenuated as a result of receiving\n                      <jats:italic>iKIR<\/jats:italic>\n                      siRNA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      <jats:italic>iKIR<\/jats:italic>\n                      knockdown stimulates NK cells and promotes their antifibrogenic activity in mice and human co-cultures. These findings have implications for possible immune therapeutic strategies in patients with advanced liver disease.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/gut.2010.211136","type":"journal-article","created":{"date-parts":[[2010,7,26]],"date-time":"2010-07-26T20:51:50Z","timestamp":1280177510000},"page":"90-98","source":"Crossref","is-referenced-by-count":114,"title":["Amelioration of hepatic fibrosis by NK cell activation"],"prefix":"10.1136","volume":"60","author":[{"given":"Nidal","family":"Muhanna","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina 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