Naslov
Kupffer Cells are a major source of IL-1β and other drivers of inflammation in Chronic Hepatitis C

Autori
Papić, Neven ; Delker, Don ; Rong, Xia ; Liu, Shuanghu ; Negash, Amina ; Gale, Michael Jr ; Hagedorn, Curt

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Hepatology Supplement: The 63rd Annual Meeting of the American Association for the Study of Liver Diseases: / - : Wiley-Blackwell, 2012, IiA-vA

Skup
The 63rd Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2012

Mjesto i datum
Boston (MA), Sjedinjene Američke Države, 08.12.2012. - 13.12.2012

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
HCV; inflammation; Kupffer cells; IL1; inflammasome

Sažetak
Background: Inflammation and fibrogenesis are hallmarks of long- term chronic infection with the hepatitis C virus (HCV) in most patients. Purpose: To determine the cell sources of cytokines and chemokines driving inflammation and responses leading to fibrogenesis in HCV infected liver, we evaluated inflammatory signaling and responses from hepatocytes and Kupffer cells, the liver macrophage. We performed a comprehensive RNA sequencing gene expression analysis of models of hepatocytes (Huh7 cells) and Kupffer cells (THP1 cells), - and + HCV, plus mild (inflammation but no fibrosis) and severe (cirrhosis) chronic hepatitis C liver biospecimens. Methods: Poly(A)+ RNA from three HCV infected, mock infected or LPS stimulated human macrophage cells (THP-1), or Huh7 cells -/+ HCV were isolated at timepoints post virus exposure. Gene-expression was measured by RNA-seq analysis (Illumina) (see Viruses 2012 ; 4:581). Similar analysis was done with mild (inflammation, no fibrosis) and severe (cirrhosis) hepatitis C liver biospecimens. Results: We found that macrophages can injest HCV virions through phagocytic uptake of cell-free virus. While HCV infection of Huh7 cells induced small changes in proinflammtory gene expression, HCV uptake by macrophages induced marked changes in proinflammatory gene expression after virus exposure. Macrophages (THP-1) overall displayed 10, 047 and 9, 787 genes that were differentially expressed (1.5X change and FDR 13) at 6 and 16 hours post HCV exposure, respectively. Remarkably, we found a dramatic and broad increase in IL1b and NFκB responsive proinflammatory cytokine and chemokines expression induced by HCV in macrophages (IL1b, 22X ; IL12, 132X increase ; IL6, 72X ; IL8, 38X ; MIP1b or CCL4, 34 ; MIP1a or CCL3, 24X ; RANTES, 4X). Analysis of genes in the cytokine and chemokine pathways showed increased IL1b levels with increasing severity of liver disease and marked overlap in upregulated expression of these pathways in macrophages exposed to HCV and chronic hepatitis C liver biospecimens. Pathway analysis was also notable for an induction of the transcription network (>200 genes) and included FOXQ1 (23X), NKX3-1 (10X) and MYB (4X). Conclusions: These results provide evidence that Macrophage-Kupffer cell IL1b plus IL1b responsive cytokines and chemokines play a major role in driving inflammation and probably fibrogenesis during chronic hepatitis C infection. Understanding the mechanisms of HCV activation of IL1b production by Kupffer cells is likely to provide new approaches to inhibiting inflammation and disease progression in chronic hepatitis C and perhaps other liver diseases.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA