C5aR, TNF-α, and FGL2 contribute to coagulation and complement activation in virus-induced fulminant hepatitis

Li, Jianjun; Tan, Yulong; Zhang, Jinyu; Zou, Liyun; Deng, Guohong; Xu, Xueqing; Wang, Rui; Ma, Zhigui; Zhang, Jue; Zhao, Tingting; Liu, Yunlai; Li, Yongsheng; Zhu, Bo; Guo, Bo

doi:10.1016/j.jhep.2014.08.050

Cited by 54 publications

(62 citation statements)

References 54 publications

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“…Previous studies suggested fgl2 played a vital role in this process with a 15-40% increase of survival when fgl2 was deleted (12,15,27,28). Multiple inflammatory factors or mediators including TNF-α and IFN-γ, IL-1β and C5aR have been demonstrated to promote FH progression with significant discrepancies between liver damage and survival rate (29)(30)(31)(32), which is accordant with our observation that CC10 substantially alleviated liver injury though survival rate improved mildly. The survival rate based on hours may be more accurate to examine the effect of CC10 on FH.…”

Section: Discussionsupporting

confidence: 90%

Clara Cell 10 kDa Protein Alleviates Murine Hepatitis Virus Strain 3-Induced Fulminant Hepatitis by Inhibiting Fibrinogen-Like Protein 2 Expression

Liu

Wang

et al. 2018

Front. Immunol.

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Background: Fulminant hepatitis (FH) is a serious threat to human life, accompanied by massive and rapid necroinflammation. Kupffer cells, the major immune cell population involved in innate immune responses, are considered to be central for FH. Fibrinogen-like protein 2 (Fgl2) is a pro-coagulant protein that is substantially induced in macrophages upon viral infection, and Fgl2 depletion represses murine hepatitis virus strain 3 (MHV-3) infection. Clara cell 10 kDa (CC10) protein is a secretory protein with anti-inflammatory properties in allergic rhinitis and asthma. However, its mechanisms of action and pathogenic roles in other disease are still unclear. In this study, we aimed to determine the role of CC10 in FH and the regulation of Fgl2 by CC10.Methods: A mouse FH model was established by peritoneal injection of MHV-3. The mice received CC10 protein through tail vein injection before viral infection. Survival rate, liver function, liver histology, fibrin deposition, and necrosis were examined. The regulatory effect of CC10 on Fgl2 expression was investigated using THP-1 cells and mouse peritoneal macrophages in vitro.Results: In the mouse FH model induced by MHV-3, the survival rate increased from 0 to 12.5% in the CC10 group compared to that in the saline-only control group. Meanwhile, the levels of ALT and AST in serum were significantly decreased and liver damage was reduced. Furthermore, hepatic Fgl2, TNF-α, and IL-1β expression was obviously downregulated together with fibrin deposition, and hepatocyte apoptosis was reduced after administration of CC10 protein. In vitro, CC10 was found to significantly inhibit the expression of Fgl2 in IFN-γ-treated THP-1 cells and MHV-3-infected mouse peritoneal macrophages by western blot and real-time PCR. However, there was no direct interaction between CC10 and Fgl2 as shown by co-immunoprecipitation. Microarray investigations suggested that HMG-box transcription factor 1 (HBP1) was significantly low in CC10-treated and IFN-γ-primed THP-1 cells. HBP1-siRNA treatment abrogated the inhibitory effect of CC10 on Fgl2 expression in Human Umbilical Vein Endothelial cells (HUVECs).Conclusion:CC10 protects against MHV-3-induced FH via suppression of Fgl2 expression in macrophages. Such effects may be mediated by the transcription factor HBP1.

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Section: Discussionsupporting

confidence: 90%

Clara Cell 10 kDa Protein Alleviates Murine Hepatitis Virus Strain 3-Induced Fulminant Hepatitis by Inhibiting Fibrinogen-Like Protein 2 Expression

Liu

Wang

et al. 2018

Front. Immunol.

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“…Fgl2, a member of the fibrinogen super family, possesses prothrombinase activity and immune regulatory functions in a variety of conditions including viral-induced inflammation, xenograft rejection, chronic obstructive pulmonary disease and abortion 3-6. In the previous studies, Fgl2 has been showed to play a multimodal role in the innate and acquired immune system, acting as an effect molecular of Treg cells, suppressing T cell proliferation, inducing apoptosis in B cells, promoting macrophage activation and inhibiting maturation of dendritic cells (DCs) 4, 7-9.…”

Section: Introductionmentioning

confidence: 99%

Stroma-derived Fibrinogen-like Protein 2 Activates Cancer-associated Fibroblasts to Promote Tumor Growth in Lung Cancer

Zhu¹,

Zhang²,

Zha³

et al. 2017

Int. J. Biol. Sci.

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Fibrinogen-like protein 2 (Fgl2), a member of the fibrinogen super family, is a pleiotropic cytokine that impacts diverse cellular functions. Previous studies have shown that tumor cell-derived Fgl2 promotes tumorigenesis and metastasis in immune-deficient mice, and it also functions as an immune-suppressive modulator in glioblastoma multiform (GMB). This study aimed to evaluate whether and how tumor stroma-derived Fgl2 affects tumorigenesis and tumor progression. We established the syngeneic transplantable Lewis lung carcinoma (LLC) model in Fgl2-knock-out (Fgl2-KO) mice and we found that deficiency of host Fgl2 is associated with reduced growth of syngeneic LLC tumors. Furthermore, we confirmed that host Fgl2 deficiency significantly decreased the accumulation of myeloid-derived suppressor cells (MDSCs) through down-regulation of chemokine (C-X-C motif) ligand 12 (CXCL12) expression. More importantly, we demonstrated that Fgl2 induced an activated and pro-tumorigenic phenotype of cancer-associated fibroblasts (CAFs) which are the principal source of CXCL12 in the tumor microenvironment (TME). Our results present a novel role of stroma-derived Fgl2 in CAF activation and function, suggesting that Fgl2 is an effective therapeutic target for treating lung cancer.

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“…KEGG pathway analysis revealed that the immune response-associated proteins were mainly clustered at complement and coagulation cascades. To our knowledge, the deficiency of complement significantly reduces IL-1 β levels [21, 22], and TNF- α contributes to coagulation and complement activation in virus-induced fulminant hepatitis [23], accounting for the upregulation of IL-1 β and TNF- α levels in YDH syndrome individuals. Based on these findings, we speculated that the abnormally expressed proteins involved in complement and coagulation cascades disrupted the signaling pathways related to immune response.…”

Section: Discussionmentioning

confidence: 99%

Serum Protein KNG1, APOC3, and PON1 as Potential Biomarkers for Yin‐Deficiency‐Heat Syndrome

Liu

Mao

Ping

et al. 2016

Evidence-Based Complementary and Alternative Medicine

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Yin-deficiency-heat (YDH) syndrome is a concept in Traditional Chinese Medicine (TCM) for describing subhealth status. However, there are few efficient diagnostic methods available for confirming YDH syndrome. To explore the novel method for diagnosing YDH syndrome, we applied iTRAQ to observe the serum protein profiles in YDH syndrome rats and confirmed protein levels by ELISA. A total of 92 differentially expressed proteins (63 upregulated proteins and 29 downregulated proteins), which were mainly involved in complement and coagulation cascades and glucose metabolism pathway, were identified by the proteomic experiments. Kininogen 1 (KNG1) was significantly increased (p < 0.0001), while apolipoprotein C-III (APOC3, p < 0.005) and paraoxonase 1 (PON1, p < 0.001) were significantly decreased in the serum of YDH syndrome rats. The combination of KNG1, APOC3, and PON1 constituted a diagnostic model with 100.0% sensitivity and 85.0% specificity. The results indicated that KNG1, APOC3, and PON1 may act as potential biomarkers for diagnosing YDH syndrome. KNG1 may regulate cytokines and chemokines release in YDH syndrome, and the low levels of PON1 and APOC3 may increase oxidative stress and lipolysis in YDH syndrome, respectively. Our work provides a novel method for YDH syndrome diagnosis and also provides valuable experimental basis to understand the molecular mechanism of YDH syndrome.

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C5aR, TNF-α, and FGL2 contribute to coagulation and complement activation in virus-induced fulminant hepatitis

Cited by 54 publications

References 54 publications

Clara Cell 10 kDa Protein Alleviates Murine Hepatitis Virus Strain 3-Induced Fulminant Hepatitis by Inhibiting Fibrinogen-Like Protein 2 Expression

Clara Cell 10 kDa Protein Alleviates Murine Hepatitis Virus Strain 3-Induced Fulminant Hepatitis by Inhibiting Fibrinogen-Like Protein 2 Expression

Stroma-derived Fibrinogen-like Protein 2 Activates Cancer-associated Fibroblasts to Promote Tumor Growth in Lung Cancer

Serum Protein KNG1, APOC3, and PON1 as Potential Biomarkers for Yin‐Deficiency‐Heat Syndrome

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