Properdin and Factor H: Opposing Players on the Alternative Complement Pathway “See-Saw”

Abstract

Properdin and factor H are two key regulatory proteins having opposite functions in the alternative complement pathway. Properdin up-regulates the alternative pathway by stabilizing the C3bBb complex, whereas factor H downregulates the pathway by promoting proteolytic degradation of C3b. While factor H is mainly produced in the liver, there are several extrahepatic sources. In addition to the liver, factor H is also synthesized in fetal tubuli, keratinocytes, skin fibroblasts, ocular tissue, adipose tissue, brain, lungs, heart, spleen, pancreas, kidney, muscle, and placenta. Neutrophils are the major source of properdin, and it is also produced by monocytes, T cells and bone marrow progenitor cell line. Properdin is released by neutrophils from intracellular stores following stimulation by N-formyl-methionine-leucine-phenylalanine (fMLP) and tumor necrosis factor alpha (TNF-α). The HEP G2 cells derived from human liver has been found to produce functional properdin. Endothelial cells also produce properdin when induced by shear stress, thus is a physiological source for plasma properdin. The diverse range of extrahepatic sites for synthesis of these two complement regulators suggests the importance and need for local availability of the proteins. Here, we discuss the significance of the local synthesis of properdin and factor H. This assumes greater importance in view of recently identified unexpected and novel roles of properdin and factor H that are potentially independent of their involvement in complement regulation.

Insights into the Effects of Complement Factor H on the Assembly and Decay of the Alternative Pathway C3 Proconvertase and C3 Convertase

“…C3bBb(Mg 2ϩ ) C3 Convertase Formation and Decay in the Presence of Properdin-To evaluate the ability of P to stabilize C3bBb(Mg 2ϩ ) formation and decay, the complexes were generated by incubating C3b-coated wells with FB (1000 ng/ml), FD (5 ng/ml), and P (114.5 ng/ml; molar ratio FB/P ϭ 5:1) (35) in the presence or in the absence of FH (2640 ng/ml; molar ratio FB/FH ϭ 1:1.6) for 10 min at 25°C (Fig. 1E).…”

Innate immune humoral factors, C1q and factor H, with differential pattern recognition properties, alter macrophage response to carbon nanotubes

“…In the alternative pathway, hydrolysis of a thiol-ester in C3 to form C3(H 2 O) results in formation of a complex with factor B, which is cleaved by factor D, to form A C C E P T E D M A N U S C R I P T inhibiting interaction with factor B, and then factor I, a regulatory protease, cleaves C3b in the C3b-FH complex to form iC3b, a potent opsonin, which is unable to form C3bBb [10][11][12].…”

Effect of the protein corona on nanoparticles for modulating cytotoxicity and immunotoxicity

“…As a consequence, the suggested process can inhibit alternative complement pathways. 66 In this study, hybrid polymeric structures of NPs with methoxyl surface groups bind with complement deactivating proteins (fH) and, thus, induce the lowest complement activation. 65 Thus, attached fH on NPs can down-regulate signal pathways in the complement system via the alternative pathway by controlling surface chemical modification.…”