Complement has been implicated in liver repair after toxic injury. Here, we demonstrate that complement components are essential for liver regeneration, and mediate their effect by interacting with key signaling networks that promote hepatocyte proliferation. C3- or C5-deficient mice exhibited high mortality, parenchymal damage, and impaired liver regeneration after partial hepatectomy. Mice with dual C3 and C5 deficiency had a more exacerbated phenotype that was reversed by combined C3a and C5a reconstitution. Interception of C5a receptor signaling resulted in suppression of IL-6/TNFα induction and lack of C3 and C5a receptor stimulation attenuated nuclear factor–κB/STAT-3 activation after hepatectomy. These data indicate that C3a and C5a, two potent inflammatory mediators of the innate immune response, contribute essentially to the early priming stages of hepatocyte regeneration.

Although the complement system has been implicated in liver regeneration after toxic injury and partial hepatectomy, the mechanism or mechanisms through which it participates in these processes remains ill-defined. In this study, we demonstrate that complement activation products (C3a, C3b/iC3b) are generated in the serum of experimental mice after CCl4 injection and that complement activation is required for normal liver regeneration. Decomplementation by cobra venom factor resulted in impaired entry of hepatocytes into S phase of the cell cycle. In addition, livers from C3-deficient (C3−/−) mice showed similarly impaired proliferation of hepatocytes, along with delayed kinetics of both hepatocyte hyperplasia and removal of injured liver parenchyma. Restoration of hepatocyte proliferative capabilities of C3−/− mice through C3a reconstitution, as well as the impaired regeneration of C3a receptor-deficient mice, demonstrated that C3a promotes liver cell proliferation via the C3a receptor. These findings, together with data showing two waves of complement activation, indicate that C3 activation is a pivotal mechanism for liver regeneration after CCl4 injury, which fulfills multiple roles; C3a generated early after toxin injection is relevant during the priming of hepatocytes, whereas C3 activation at later times after CCl4 treatment contributes to the clearance of injured tissue.

Purpose: Recent work points out a role of B7H3, a member of the B7-family of costimulatory proteins, in conveying immunosuppression and enforced invasiveness in a variety of tumor entities. Glioblastoma is armed with effective immunosuppressive properties resulting in an impaired recognition and ineffective attack of tumor cells by the immune system. In addition, extensive and diffuse invasion of tumor cells into the surrounding brain tissue limits the efficacy of local therapies. Here, 4IgB7H3 is assessed as diagnostic and therapeutic target for glioblastoma.Experimental Design: To characterize B7H3 in glioblastoma, we conduct analyses not only in glioma cell lines and glioma-initiating cells but also in human glioma tissue specimens.Results: B7H3 expression by tumor and endothelial cells correlates with the grade of malignancy in gliomas and with poor survival. Both soluble 4IgB7H3 in the supernatant of glioma cells and cell-bound 4IgB7H3 are functional and suppress natural killer cell-mediated tumor cell lysis. Gene silencing showed that membrane and soluble 4IgB7H3 convey a proinvasive phenotype in glioma cells and glioma-initiating cells in vitro. These proinvasive and immunosuppressive properties were confirmed in vivo by xenografted 4IgB7H3 gene silenced glioma-initiating cells, which invaded significantly less into the surrounding brain tissue in an orthotopic model and by subcutaneously injected LN-229 cells, which were more susceptible to natural killer cell-mediated cytotoxicity than unsilenced control cells.Conclusions: Because of its immunosuppressive and proinvasive function, 4IgB7H3 may serve as a therapeutic target in the treatment of glioblastoma.