Cytokines predict virological response in chronic hepatitis B patients receiving peginterferon alfa-2a therapy

BACKGROUND Chronic hepatitis B virus infection remains a major global public health problem.Peginterferon-alpha-2a(PEG-IFN)has direct antiviral and immunoregulatory effects,and it has become one of the first choice drugs for the treatment of chronic hepatitis B(CHB).Cytokines play an important role in immunity,and they directly inhibit viral replication and indirectly determine the predominant pattern of the host immune response.AIM To determine the correlation between cytokine/chemokine expression levels and response to PEG-IFN treatment in patients with CHB.METHODS Forty-six kinds of cytokines were analyzed before PEG-IFN therapy and at 24 wk during therapy in 26 CHB patients.RESULTS The monokine induced by INF-γ(CXCL9)and serum interferon-inducible protein 10(IP-10)levels at baseline were higher in virological responders than in nonvirological responders(NRs)and decreased during treatment,whereas the NRs did not exhibit significant changes.The macrophage inflammatory protein 1d(MIP-1d)levels at baseline and during treatment were significantly higher in the virological responders than in the NRs,while thymus and activation-regulated chemokine(TARC)levels at baseline and during treatment were significantly lower in the virological responders than in the NRs.The CXCL9,IP-10,MIP-1d,and TARC baseline levels exhibited the expected effects for interferon treatment.The area under the receiver operating characteristic curve values of CXCL9,IP-10,MIP-1d,and TARC for predicting virological responses were 0.787,0.799,0.787,and 0.77(P=0.01,0.013,0.01,and 0.021),respectively.CONCLUSION We found that cytokine levels before and during treatment may represent potential biomarkers to select CHB patients who can respond to PEG-IFN.Therefore,cytokines can be used as an indicator of antiviral drug selection before CHB treatment.

Sustained induction of IP-10 by MRP8/14 via the IFNβ-IRF7 axis in macrophages exaggerates lung injury in endotoxemic mice

Background:As a damage-associated molecular pattern,the myeloid-related protein 8/14(MRP8/14)heterodimer mediates various inflammatory diseases,such as sepsis.However,how MRP8/14 promotes lung injury by regulating the inflammatory response during endotoxemia remains largely unknown.This study aims at illuminating the pathological functions of MRP8/14 in endotoxemia.Methods:An endotoxemic model was prepared with wild-type and myeloid cell-specific Mrp8 deletion(Mrp8MC)mice for evaluating plasma cytokine levels.Lung injury was evaluated by hematoxylin and eosin(H&E)staining,injury scoring and wet-to-dry weight(W/D)ratio.The dynamic profile of interferonγ(IFNγ)-inducible protein 10(IP-10)mRNA expression induced by macrophage MRP8/14 was determined by quantitative real-time polymerase chain reaction(qPCR).Immunoblotting was used to evaluate the increase in IP-10 level induced by activation of the JAK-STAT signaling pathway.Luciferase reporter assay was performed to detect the involvement of IRF7 in Ip-10 gene transcription.In vivo air pouch experiments were performed to determine the biological function of IP-10 induced by MRP8/14.Results:Experiments with Mrp8MC mice showed that MRP8/14 promoted the production of cytokines,including IP-10,in the bronchoalveolar lavage fluid(BALF)and lung injury in endotoxic mice.The result of qPCR showed sustained expression of Ip-10 mRNA in macrophages after treatment with MRP8/14 for 12 h.Neutralization experiments showed that the MRP8/14-induced Ip-10 expression in RAW264.7 cells was mediated by extracellular IFNβ.Western blotting with phosphorylation-specific antibodies showed that the JAK1/TYK2-STAT1 signaling pathway was activated in MRP8/14-treated RAW264.7 cells,leading to the upregulation of Ip-10 gene expression.IRF7 was further identified as a downstream regulator of the JAK-STAT pathway that mediated Ip-10 gene expression in macrophages treated with MRP8/14.In vivo air pouch experiments confirmed that the IFNβ-JAK1/TYK2-STAT1-IRF7 pathway was required for chemokine(C-X-C motif)receptor 3(CXCR3)+T lymphocyte migration,which promoted lung injury in the context of endotoxemia.Conclusions:In summary,our study demonstrates that MRP8/14 induces sustained production of IP-10 via the IFNβ-JAK1/TYK2-STAT1-IRF7 pathway to attract CXCR3+T lymphocytes into lung tissues and ultimately results in lung injury by an excessive inflammatory response in the context of endotoxemia.