Modulation of complement gene expression by glucocorticoids

Abstract

The addition of dexamethasone, prednisolone or cortisol (in order of efficacy) to human monocytes in culture produced dose-related increases in the synthesis rates of the complement components C1 inhibitor (C1-inh), factor B (B) and C2. In contrast, concentrations of C3 and lysozyme in the culture supernatants were decreased. Indomethacin stimulated synthesis of C1-inh, C2 and B, but had little effect on synthesis of C3 or lysozyme. The simultaneous addition of cycloheximide (2.5 micrograms/ml) abrogated the effects of dexamethasone on synthesis of C2, B and C1-inh, but the effect of indomethacin on the synthesis of these components was unchanged. These data suggest that protein synthesis is required for the effects of glucocorticoids on the synthesis of C2, B and C1-inh to occur. Dexamethasone and indomethacin increased the abundances of C1-inh mRNA, B mRNA and C2 mRNA in parallel with changes in the synthesis rates of these proteins. The changes in mRNA abundance were not transcriptional, but were shown to be due to increased mRNA stability. In contrast, dexamethasone decreased the expression of C3 and lysozyme by decreasing the rate of transcription of these genes. Indomethacin had no effect on transcription of the C3 and lysozyme genes. The half-lives of C3 mRNA, lysozyme mRNA and actin mRNA were not altered by dexamethasone or indomethacin. It is concluded that the effects of glucocorticoids on monocyte synthesis of C2, B and C1-inh are due to increased mRNA stability and may be related to inhibition of prostaglandin synthesis, as these effects are similar to those produced by indomethacin. The effects of dexamethasone on the synthesis of C3 and lysozyme differ from those on C2, B and C1-inh as they depend upon a decrease in gene transcription, which is not affected by indomethacin.

Corticosterone–immune interactions during captive stress in invading Australian cane toads (Rhinella marina)

“…The authors attributed this to a tradeoff due to higher energetic demands in breeding individuals (French et al, 2010), consistent with the view that stress-associated, shortterm immunomodulation is adaptive and context-dependent (French et al, 2009;Sapolsky et al, 2000). Complement lytic action is a powerful and non-specific inflammatory component of innate immunity, and is among the immune factors hypothesized to be brought under control by the glucocorticoid stress response to avoid damage to self-tissue (Lappan and Whaley, 1991;Sapolsky et al, 2000). As an important contributor to inflammation and fever (Blatteis et al, 2000) -two of the most energetically costly immune functions (Nelson, 2004) complement is also a likely target of immune trade-offs modulated by the HPA axis.…”

Serum haemolytic and agglutinating activity as indicators of fish immunocompetence: their suitability in stress and dietary studies

“…Thus, ingested lipids may modify fatty acid composition of membrane phospholipids, production of eicosanoids, alter the physical properties of cell membranes and alter the activity of membraneassociated receptors (Sheldon and Blazer, 1991). Concerning the parameters chosen in the present work, the induction mechanism for the changes in agglutination and lytic activities is not known at present, although it has been shown in mammals that glucocorticoids affect the synthesis of the C3 component of the complement system by a decrease in gene transcription (Lappin and Whaley, 1991). In other work, Li and Lowell (1985) showed complement inhibition by reduction of its component C1Q.…”

Complement levels and activity in the normal and LPS-injured lung

“…These changes could be an indirect response to cytokines, to other inflammatory mediators, or possibly even to complement proteins leaking into the lung from the serum. IFN-␥, IL-6-type cytokines, IL-1-type cytokines, hormones, LPS, and C5a have all been reported to effect complement expression both in vivo and by cultured cells (14,15,24,27,35,36,40,52). Detailed analyses of promoters and enhancers for factor B and C3 have demonstrated the intricate control by individual cytokines through specific regulatory sequences (21,22,23,50).…”

“…The expression of several complement components increases during the acute phase, a period of systemic inflammation marked by increases in liver synthesis of certain proteins (37). In vitro, cytokines, hormones, and lipopolysaccharide (LPS) are able to modulate complement expression (14,15,24,27,35,40,52, and reviewed in Ref. 44).…”