Protein Kinase Cα Regulates the Expression of Complement Receptor Ig in Human Monocyte–Derived Macrophages

Abstract

The complement receptor Ig (CRIg) is selectively expressed by macrophages. This receptor not only promotes the rapid phagocytosis of bacteria by macrophages but also has anti-inflammatory and immunosuppressive functions. Previous findings have suggested that protein kinase C (PKC) may be involved in the regulation of CRIg expression in human macrophages. We have now examined the role of PKCα in CRIg expression in human monocyte-derived macrophages (MDM). Macrophages nucleofected with plasmid containing short hairpin RNA against PKCα showed markedly reduced expression of PKCα, but normal PKCζ expression, by Western blotting analysis, and vice versa. PKCα-deficient MDM showed increased expression of CRIg mRNA and protein (both the long and short form), an increase in phagocytosis of complement-opsonized Candida albicans, and decreased production of TNF-α and IL-6. TNF-α caused a marked decrease in CRIg expression, and addition of anti-TNF mAb to the TNF-α–producing MDMs increased CRIg expression. PKCα-deficient macrophages also showed significantly less bacterial LPS-induced downregulation of CRIg. In contrast, cells deficient in PKCα showed decreased expression of CR type 3 (CR3) and decreased production of TNF-α and IL-6 in response to LPS. MDM developed under conditions that increased expression of CRIg over CR3 showed significantly reduced production of TNF-α in response to opsonized C. albicans. The findings indicate that PKCα promotes the downregulation of CRIg and upregulation of CR3 expression and TNF-α and IL-6 production, a mechanism that may promote inflammation.

CRIg-expressing peritoneal macrophages are associated with disease severity in patients with cirrhosis and ascites

“…Consistent with CRIg's antiinflammatory functions, VSIG4 gene expression is upregulated by antiinflammatory stimuli such as IL-10 and dexamethasone and downregulated by proinflammatory stimuli such as IFN-γ and TNF in vitro and in vivo (48)(49)(50). Although increased transcription and translation could conceivably contribute to the CRIg induction we observed in ascites fluid, other as-yet-unknown factors regulating surface CRIg expression are likely involved.…”

An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice

“…Anti-CRIg mAb did not detect endogenous CRIg in mouse brain (Fig. 3D), likely because of low expression in brain parenchyma (23). Together, these data demonstrate that CD59-2a-CRIg localizes to areas of complement activation and inhibits MAC deposition in vivo.…”

Expression of Complement Receptor Immunoglobulin in Human Monocyte-Derived Macrophages

“…They suggest that agents regulate the expression via PKC . 6 Dexamethasone is a synthetic glucocorticoid compound with potent anti-inflammatory properties. 12 Dexamethasone is used to treat inflammatory and autoimmune conditions such as rheumatoid arthritis, allergic reactions, and certain skin disorders.…”

“…6 In order to investigate the significance of GR/NR3C1 on CRIg/VSIG4 expression, the expression of CRIg/VSIG4 under GR/NR3C1-silenced condition using shRNA transfection method. GR/NR3C1-deficient macrophages show significantly decreased expression of mRNA and protein levels, compared to untreated control, reagent control, and scramble shRNAtransfected (p < 0.01).…”

“…Evidence suggested that dexamethasone regulate CRIg expression via protein kinase Cα and also inhibit the activation of arachidonate. 6 It is interesting that glucocorticoid receptor agonist not only has ability to decrease inflammation but also can up-regulate CRIg expression. However, the signaling pathway of GR regulate CRIg expression remain unclear.…”