MAPKAP kinase 2 regulates IL-10 expression and prevents formation of intrahepatic myeloid cell aggregates during cytomegalovirus infections

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• 作者：Christian Ehlting¹ ; Mirko Trilling² ; ⁴ ; Christopher Tiedje³ ; Vu Thuy Khanh Le-Trilling² ; ⁴ ; Ute Albrecht¹ ; Stefanie Kluge¹ ; Albert Zimmermann⁴ ; Dirk Graf¹ ; Matthias Gaestel³ ; Hartmut Hengel⁵ ; Dieter Hä ; ussinger¹ ; Johannes Georg Bode¹ ; ^{Johannes.Bode@med.uni-duesseldorf.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CMV ; cytomegalovirus ; dpi ; days post infection ; hpi ; hours post infection ; IL ; interleukin ; MAPK ; mitogen activated protein kinase ; MCMV ; mouse cytomegalovirus ; MOI ; multiplicity of infection ; LPS ; lipopolysaccharide ; MKK ; MAPK kinase ; MK ; MAPK-activated protein kinase ; TTP ; tristetraprolin ; IFN ; Interferon
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：64
• 期：2
• 页码：380-389
• 全文大小：1861 K

文摘

The kinase p38^MAPK and its downstream target MAPKAP kinase (MK) 2 are critical regulators of inflammatory responses towards pathogens. To date, the relevance of MK2 for regulating IL-10 expression and other cytokine responses towards cytomegalovirus (CMV) infection and the impact of this pathway on viral replication in vitro and in vivo is unknown and the subject of this study.

Methods

The effect of MK2, interferon-α receptor (IFNAR)1, tristetraprolin (TTP) and IL-10 on mouse (M)CMV virus titres, cytokine expression, signal transduction, transcript stability, liver enzymes release, immune cell recruitment and aggregation in response to MCMV infection were studied ex vivo in hepatocytes and macrophages, as well as in vivo.

Results

MK2 is critical for MCMV-induced production of IL-10, IFN-α2 and 4, IFN-β, IL-6, and TNF-α but not for IFN-γ. The MCMV-induced IL-10 production requires activation of IFNAR1 and is further regulated by MK2 and TTP-dependent stabilization of IL-10 transcripts. MK2^−/− mice are able to control acute MCMV replication, despite deregulated cytokine production. This may be related to the observation that MCMV-infected MK2^−/− mice show enhanced formation of focal intrahepatic lymphocyte infiltrates resembling intrahepatic myeloid cell aggregates of T cell expansion (iMATEs), which were also observed in MCMV-infected IL-10^−/− mice but are almost absent in MCMV-infected wild-type controls.

Conclusions

The data suggest that MK2 is critical for regulating cytokine responses towards acute MCMV infection, including that of IL-10 via IFNARI-mediated circuits. MCMV stimulates expression of MK2-dependent cytokines, in particular IL-10 and thereby prevents enhanced formation of intrahepatic iMATE-like cellular aggregates.