Disease relevance of C3

• Complement C4 is protective for lupus disease independent of C3 [1].
• We induced the passive reverse Arthus reaction to IgG immune complexes (IC) at different tissue sites in mice lacking C3 treated or not with a C5aR-specific antagonist, or in mice lacking mast cells (Kit(W)/Kit(W-v) mice), and compared the inflammatory responses with those in the corresponding wild-type mice [2].
• The role of complement C3 in mediating systemic lupus erythematosus (SLE) was examined using a double-knockout C3(null)C4(null) Fas (CD95)-deficient mouse model [1].
• The alternative activation pathway and complement component C3 are critical for a protective immune response against Pseudomonas aeruginosa in a murine model of pneumonia [3].
• OBJECTIVE: To investigate the effect of complement deficiency on atherogenesis and lipidemia, we used mice deficient in the third complement component (C3-/-) or factor B (FB-/-) [4].

Psychiatry related information on C3

• The third component of complement C3 and its fragments have a central role in a variety of host defense mechanisms [5].
• Further, the synthesis of C3 was increased 5-10-fold in response to various synthetic peptides corresponding to the amyloid beta/A4 protein, which is the main constituent of extracellular amyloid deposits in Alzheimer's disease (AD) [6].

High impact information on C3

• There were marked reductions in proteolysis of serum C3, deposition of C3 on organisms within SIGN-R1(+) spleen macrophages, and formation of C3 ligands [7].
• A pivotal step in the complement pathway is the assembly of a C3 convertase, which digests the C3 complement component to form microbial binding C3 fragments recognized by leukocytes [7].
• Surprisingly, conditional SIGN-R1 knockout mice developed deficits in C3 catabolism when given S. pneumoniae or its capsular polysaccharide intravenously [7].
• Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H [8].
• This pathway is triggered by the hydrolysis of C3, resulting in the formation of C3 convertase [8].

Chemical compound and disease context of C3

• Local extrahepatic expression of complement genes C3, factor B, C2, and C4 is increased in murine lupus nephritis [9].
• When challenged with allergen, mice deficient in C3 exhibit diminished airway hyperresponsiveness and lung eosinophilia [10].
• Normal mice injected with Escherichia coli LPS show a marked increase in whole kidney C3 mRNA over control (saline-injected) animals [11].
• The anti-infective activity of romurtide, a synthetic muramyl dipeptide (MDP) derivative, was evaluated in experimental pneumococcal pneumonia in mice deficient in the third component of complement (C3) [12].

Biological context of C3

• Mice with dual C3 and C5 deficiency had a more exacerbated phenotype that was reversed by combined C3a and C5a reconstitution [13].
• Interleukin 6 influences germinal center development and antibody production via a contribution of C3 complement component [14].
• C3- or C5-deficient mice exhibited high mortality, parenchymal damage, and impaired liver regeneration after partial hepatectomy [13].
• The development of severe SLE in the absence of both classical and alternative complement pathways suggests that it is the absence of C4, and not the presence of C3, that is critical in SLE pathogenesis [1].
• Collectively, these results indicate that complement activation by the alternative pathway is critical for the survival of mice infected with P. aeruginosa and that the protection provided by complement is at least in part due to C3-mediated opsonization and phagocytosis of P. aeruginosa [3].

Anatomical context of C3

• In addition, germinal center cells isolated from C3-deficient mice produced a similar defect in isotype production [14].
• The IC-mediated slow leukocyte rolling velocity and subsequent adhesion and emigration are dependent on Fcgamma receptors (FcgammaRs), particularly FcgammaRIII, with complement C3 and C5 having no detectable role [15].
• Finally, we demonstrated that C3 contributed to the elicitation of neutrophils to alveoli, which corresponded to an increased synthesis of TNF-alpha, macrophage-inflammatory protein-2, and cytokine-induced neutrophil chemoattractant [2].
• Together, the phenotypes of C3(-/-) mice and Kit(W)/Kit(W-v) mice suggest that complement and mast cells have distinct tissue site-specific requirements acting by apparently distinct mechanisms in the initiation of IC inflammation [2].
• In mice, C3 (the precursor to ASP) knockout results in ASP deficiency and leads to reduced body fat and leptin levels [16].

Associations of C3 with chemical compounds

• Our initial study indicated that complement C3-deficient (-/-) mice (and, therefore, ASP deficient) demonstrated altered dietary postprandial triglyceride clearance [17].
• Ovarian steroid-regulated synthesis and secretion of complement C3 and factor B in mouse endometrium during the natural estrous cycle and pregnancy period [18].
• Expression of C3 was remarkably enhanced, whereas that of Bf changed only slightly, after injection of combined estrogen and progesterone to ovariectomized animals [18].
• These factors have been shown to influence the formation of acylation-stimulating protein (ASP), a cleavage product of complement C3 [19].
• Both human and murine adipocytes express mRNA and/or protein for the complement components C3 and factors B and D (adipsin) required to generate ASP [20].

Physical interactions of C3

• Distinct tissue site-specific requirements of mast cells and complement components C3/C5a receptor in IgG immune complex-induced injury of skin and lung [2].

Regulatory relationships of C3

• Acylation-stimulating protein (ASP) deficiency induces obesity resistance and increased energy expenditure in ob/ob mice [16].
• Cis- and trans-acting elements required for constitutive and cytokine-regulated expression of the mouse complement C3 gene [21].
• Synthetic Alzheimer amyloid beta/A4 peptides enhance production of complement C3 component by cultured microglial cells [6].

Other interactions of C3

• A second alteration involved impaired de novo synthesis of C3 both in serum and germinal center cells from IL-6-deficient mice [14].
• Factor B(-/-) mice, but not C4(-/-) mice, infected with P. aeruginosa had a mortality rate similar to that of C3(-/-) mice, indicating that in this model the alternative pathway of complement activation is required for the host defense against Pseudomonas infection [3].
• The C3-/- mice also had 58% higher serum triglyceride levels (P<0.05) and a more proatherogenic lipoprotein profile, with significantly more low-density lipoprotein cholesterol and very-low-density lipoprotein triglycerides than control mice [4].
• We have recently shown that mouse erythrocytes deficient in the membrane C3 regulatory protein, complement receptor 1-related gene/protein y (Crry), but not decay-accelerating factor (DAF), were spontaneously eliminated in vivo by complement [22].
• Anti-GBM antibody administration in sensitised wild-type mice resulted in deposition of immune complexes and complement factor 3, followed by increased ICAM-1 and VCAM-1 expression and influx of polymorphonuclear leucocytes [23].

Analytical, diagnostic and therapeutic context of C3

• Plasma leptin levels were significantly reduced in C3(-/-) mice on both high (P < 0.001) and low fat diets (P < 0.01) [17].
• A probe for complement component 3 (C3-1), genetically known to be several cM distal to the t complex, was found by in situ hybridization to lie in band E1 [24].
• Western blot analysis using an antibody against C3 confirmed the cross-reactivities between anti-C3 antibody with ETF-3 and anti-ETF-3 antibody with C3 and its derivatives, C3b and iC3b [25].
• Cross-sectional studies of humans have reported correlations between C3 and obesity [26].
• This longitudinal study explored whether C3 predicts a large weight gain in middle-aged men [26].

References