Interferon regulatory factor 3 and type I interferons are protective in alcoholic liver injury in mice by way of crosstalk of parenchymal and myeloid cells
Authors
Petrasek, JanDolganiuc, Angela
Csak, Timea
Nath, Bharath D.
Hritz, Istvan
Kodys, Karen
Catalano, Donna
Kurt-Jones, Evelyn A.
Mandrekar, Pranoti
Szabo, Gyongyi
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDepartment of Medicine, Division of Gastroenterology
Document Type
Journal ArticlePublication Date
2011-01-29Keywords
Liver Diseases, AlcoholicImmunity, Innate
Interferon Type I
Interferon Regulatory Factor-3
Gastroenterology
Metadata
Show full item recordAbstract
Alcoholic liver disease (ALD) features increased hepatic exposure to bacterial lipopolysaccharide (LPS). Toll-like receptor-4 (TLR4) recognizes LPS and activates signaling pathways depending on MyD88 or TRIF adaptors. We previously showed that MyD88 is dispensable in ALD. TLR4 induces Type I interferons (IFNs) in an MyD88-independent manner that involves interferon regulatory factor-3 (IRF3). We fed alcohol or control diets to wild-type (WT) and IRF3 knock-out (KO) mice, and to mice with selective IRF3 deficiency in liver parenchymal and bone marrow-derived cells. Whole-body IRF3-KO mice were protected from alcohol-induced liver injury, steatosis, and inflammation. In contrast to WT or bone marrow-specific IRF3-KO mice, deficiency of IRF3 only in parenchymal cells aggravated alcohol-induced liver injury, associated with increased proinflammatory cytokines, lower antiinflammatory cytokine interleukin 10 (IL-10), and lower Type I IFNs compared to WT mice. Coculture of WT primary murine hepatocytes with liver mononuclear cells (LMNC) resulted in higher LPS-induced IL-10 and IFN-beta, and lower tumor necrosis factor alpha (TNF-alpha) levels compared to LMNC alone. Type I IFN was important because cocultures of hepatocytes with LMNC from Type I IFN receptor KO mice showed attenuated IL-10 levels compared to control cocultures from WT mice. We further identified that Type I IFNs potentiated LPS-induced IL-10 and inhibited inflammatory cytokine production in both murine macrophages and human leukocytes, indicating preserved cross-species effects. These findings suggest that liver parenchymal cells are the dominant source of Type I IFN in a TLR4/IRF3-dependent manner. Further, parenchymal cell-derived Type I IFNs increase antiinflammatory and suppress proinflammatory cytokines production by LMNC in paracrine manner. Conclusion: Our results indicate that IRF3 activation in parenchymal cells and resulting type I IFNs have protective effects in ALD by way of modulation of inflammatory functions in macrophages. These results suggest potential therapeutic targets in ALD. (HEPATOLOGY 2011;53:649-660.).Source
Petrasek, J., Dolganiuc, A., Csak, T., Nath, B., Hritz, I., Kodys, K., Catalano, D., Kurt-Jones, E., Mandrekar, P. and Szabo, G. (2011), Interferon regulatory factor 3 and type I interferons are protective in alcoholic liver injury in mice by way of crosstalk of parenchymal and myeloid cells . Hepatology, 53: 649–660. doi: 10.1002/hep.24059. Link to article on publisher's siteDOI
10.1002/hep.24059Permanent Link to this Item
http://hdl.handle.net/20.500.14038/31173PubMed ID
21274885Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1002/hep.24059