Genetic disruption of the murine complement C3 promoter region generates deficient mice with extrahepatic expression of C3 mRNA

Circolo, Antonella; Garnier, Gérard; Fukuda, Wataru; Wang, Xeufeng; Hidvegi, Tunda; Szalai, Alexander J.; Briles, David E.; Volanakis, John E.; Wetsel, Rick A.; Colten, Harvey R.

doi:10.1016/s0162-3109(99)00021-1

Cited by 160 publications

(136 citation statements)

References 39 publications

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“…C3-deficient mice were obtained from V. M. Holers (University of Colorado Health Sciences, Denver) (11). The mice were generated by intercrossing C3 ϩ/Ϫ mice at F1 during a backcross to C57BL/6 and then propagating C3 Ϫ/Ϫ progeny.…”

Section: Methodsmentioning

confidence: 99%

Requirement of activation of complement C3 and C5 for antiphospholipid antibody–mediated thrombophilia

Pierangeli¹,

Girardi²,

Vega-Ostertag³

et al. 2005

Arthritis & Rheumatism

331

215

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Objective. Antiphospholipid antibodies (aPL) have been shown to induce thrombosis, activate endothelial cells, and induce fetal loss. The pathogenesis of aPLinduced thrombosis, although not completely understood, may involve platelet and endothelial cell activation as well as procoagulant effects of aPL directly on clotting pathway components. Recent studies have shown that uncontrolled complement activation leads to fetal death in aPL-treated mice. In this study, we tested the hypothesis that aPL are responsible for activation of complement, thus generating split products that induce thrombosis.Methods. To study thrombus dynamics and adhesion of leukocytes we used in vivo murine models of thrombosis and microcirculation, in which injections of aPL were used.Results. Mice deficient in complement components C3 and C5 were resistant to the enhanced thrombosis and endothelial cell activation that was induced by aPL. Furthermore, inhibition of C5 activation using anti-C5 monoclonal antibodies prevented thrombophilia induced by aPL.Conclusion. These data show that complement activation mediates 2 important effectors of aPL, induction of thrombosis and activation of endothelial cells.

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Section: Methodsmentioning

confidence: 99%

Requirement of activation of complement C3 and C5 for antiphospholipid antibody–mediated thrombophilia

Pierangeli¹,

Girardi²,

Vega-Ostertag³

et al. 2005

Arthritis & Rheumatism

331

215

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“…Complement factor 3-, factor B-, and factor C4-null mice were maintained on C57Bl/6J backgrounds as previously described (Circolo et al 1999;Matsumoto et al 1997;Wessels et al 1995). Absence of circulating C3, C4, or factor B in each of the respective null mice was verified by protein immunoblot performed on plasma recovered from wildtype, C3-null, C4-null, and factor B-null mice ( Figure 1).…”

Section: Animal Husbandry and Surgerymentioning

confidence: 99%

Evidence for non-traditional activation of complement factor C3 during murine liver regeneration

Clark

Weymann

Hartman

et al. 2008

Molecular Immunology

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Complement signaling has been implicated as important for normal hepatic regeneration. However, the specific mechanism by which complement is activated during liver regeneration remains undefined. To address this question, we investigated the hepatic regenerative response to partial hepatectomy in wildtype mice, C3-, C4-, and factor B-null mice, and C4-null mice treated with a factor B neutralizing antibody (mAb 1379). The results showed that following partial hepatectomy, C3-null mice exhibit reduced hepatic regeneration compared to wildtype mice as assessed by quantification of hepatic cyclin D1 expression and hepatocellular DNA synthesis and mitosis. In contrast, C4-null mice and factor B-null mice demonstrated normal liver regeneration. Moreover, animals in which all of the traditional upstream C3 activation pathways were disrupted, i.e. C4-null mice treated with mAb 1379, exhibited normal C3 activation and hepatocellular proliferation following partial hepatectomy. In order to define candidate non-traditional mechanisms of C3 activation during liver regeneration, plasmin and thrombin were investigated for their abilities to activate C3 in mouse plasma in vitro. The results showed that both proteases are capable of initiating C3 activation, and that plasmin can do so independent of the classical and alternative pathways.Conclusions-These results show that C3 is required for a normal hepatic regenerative response, but that disruption of the classical-or lectin-dependent pathways (C4-dependent), the alternative pathway (factor B-dependent), or all of these pathways does not impair the hepatic regenerative response, and indicate that non-traditional mechanisms by which C3 is activated during hepatic regeneration must exist. In vitro analysis raises the possibility that plasmin may contribute to nontraditional complement activation during liver regeneration in vivo.

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“…The C3-deficient construct was generated by replacing 2.3 kb of the 5Ј flanking region and the first 105 bp of exon 1 of the C3 gene with the neomycin resistance gene as previously described (22). MRL/lpr mice deficient in C3 were derived by genetic backcrosses in which the MRL/lpr parental strain was initially mated to heterozygous (B6 ϫ129)F 1 C3-deficient mice.…”

Section: Generation Of Complement C3-deficient Mrl/lpr Micementioning

confidence: 99%

Complement Component C3 Is Not Required for Full Expression of Immune Complex Glomerulonephritis in MRL/lprMice

Sekine

Reilly

Molano

et al. 2001

The Journal of Immunology

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134

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Complement activation and tissue deposition of complement fragments occur during disease progression in lupus nephritis. Genetic deficiency of some complement components (e.g., Factor B) and infusion of complement inhibitors (e.g., Crry, anti-C5 Ab) protect against inflammatory renal disease. Paradoxically, genetic deficiencies of early components of the classical complement pathway (e.g., C1q, C4, and C2) are associated with an increased incidence of lupus in humans and lupus-like disease in murine knockout strains. Complement protein C3 is the converging point for activation of all three complement pathways and thus plays a critical role in biologic processes mediated by complement activation. To define the role of C3 in lupus nephritis, mice rendered C3 deficient by targeted deletion were backcrossed for eight generations to MRL/lpr mice, a mouse strain that spontaneously develops lupus-like disease. We derived homozygous knockout (C3−/−), heterozygous (C3+/−), and C3 wild-type (C3+/+) MRL/lpr mice. Serum levels of autoantibodies and circulating immune complexes were similar among the three groups. However, there was earlier and significantly greater albuminuria in the C3−/− mice compared with the other two groups. Glomerular IgG deposition was also significantly greater in the C3−/− mice than in the other two groups, although overall pathologic renal scores were similar. These results indicate that C3 and/or activation of C3 is not required for full expression of immune complex renal disease in MRL/lpr mice and may in fact play a beneficial role via clearance of immune complexes.

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Genetic disruption of the murine complement C3 promoter region generates deficient mice with extrahepatic expression of C3 mRNA

Cited by 160 publications

References 39 publications

Requirement of activation of complement C3 and C5 for antiphospholipid antibody–mediated thrombophilia

Requirement of activation of complement C3 and C5 for antiphospholipid antibody–mediated thrombophilia

Evidence for non-traditional activation of complement factor C3 during murine liver regeneration

Complement Component C3 Is Not Required for Full Expression of Immune Complex Glomerulonephritis in MRL/lprMice

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