Synthesis of complement by macrophages and modulation of their functions through complement activation

Abstract

During the last decade considerable progress has been made to characterize intimate functional links between macrophages, a major cellular component of immunoinflammatory responses, and the complement system representing the major humoral mediator of inflammation. Macrophages of various species and tissue sites have been shown to synthesize and release most of the complement components providing these cells with their own "pericellular" complement system. Circumstantial evidence for the assembly of both classical and alternative pathway convertases has been adduced. An intricate network of feedback loops involving endogenous and extrinsic factors operates to adjust complement production to acute requirements, for example augmenting production in the face of accelerated turnover at sites of inflammation, and returning it to baseline levels once the inflammatory stimulus has subsided, in order to maintain a fine-tuned balance. The molecular mechanisms underlying regulation of complement synthesis by macrophages are beginning to be elucidated by use of gene technology. On the other hand, complement activation products exert a number of effects on macrophages via specific surface receptors causing internalization of offending agents, microbes, and immune complexes, promotion of intracellular killing, controlling migration behavior, inducing release of potent biologic substances such as lysosomal enzymes, arachidonic acid metabolites, and interleukin 1. In these interactions, two important humoral mediator systems of inflammation, the complement system and the arachidonic acid cascade, are functionally linked at the level of the macrophage. Stimulation of the release of immunomodulating compounds from macrophages invoke a role for complement in immune regulation. This multifaceted interplay is of particular importance considering the mobility of macrophages that allows them to gain almost unrestricted access to sites of ongoing immunoinflammatory responses. The time seems to have come to abandon the petrified thinking in socalled systems as, for instance, humoral versus cellular, specific versus unspecific, and to proceed to interlocking functions guided by physiology proper.

HIV-Tat regulates macrophage gene expression in the context of neuroAIDS

“…C5a is a potent inflammatory mediator [81, 82]. C5 is synthesized by macrophages [83–86], and HIV infection increases the expression of the complement system in CNS cells [87–90]. HIV-mediated C5a production induces chemotactic responses of monocytes, macrophages, and dendritic cells [58, 91, 92].…”

Complement System in Lung Disease

“…Alveolar macrophages can synthesize complement proteins (Figure 2A). Macrophages from tissues other than the lung are also able to produce complement proteins under certain inflammatory conditions ( Figure 2C) (22). In vitro experiments by Huber-Lang and colleagues demonstrated that alveolar macrophage-derived serine proteases cleave C5 produced by epithelial cells into C5a that, when bound to its receptor C5aR, initiated inflammatory signaling cascades (23).…”

Complement-subcomponent-C1̅-inhibitor synthesis by human monocytes

“…Mononuclear phagocytes are not only highly specialized phagocytic cells, but they also synthesize and secrete a large number of biologically Abbreviations used: CraK-EDTA, rat serum diluted 1:15 in iso-osmotic veronal-buffered saline containing EDTA (40mmol-1-'); VBS, iso-osmotic veronal-buffered saline, pH 7.5, containing sodium barbitone (0.375g/1), diethylbarbituric acid (0.575g/1) and NaCl (8.5g/1); PBS, phosphate-buffered saline, pH7.4, containing K,HPO4 (0.34g/1), KH2PO4 (1.21 g/l) and NaCI (8g/1); DGVB2+, equal volumes of VBS containing CaCI, (150pmol.1-') and MgCI2 (lmmol-11); RPMI-PBS-EDTA, equal volumes of RPM 1.1640 and PBS containing EDTA (10mmol-1-'); PBS-BSA, PBS containing bovine serum albumin (1%, w/v); RPMI-FCS, RPMI.1640 containing 20O (v/v) active products (Nathan et al, 1980). Among the proteins that are secreted by these cells are components of the complement system (Colten, 1976;Hartung & Hadding, 1983). So far it has been shown that human mononuclear phagocytes synthesize CT subcomponents (Muller et al, 1978), C2 (Einstein et al, 1976) C3 (Strunk et al, 1983) and factors B, D, P, H and I of the alternative pathway (Whaley, 1980).…”