Human keratinocytes produce the complement inhibitor factor H: Synthesis is regulated by interferon-γ

Timár, Krisztina K.; Pasch, Marcel C.; Bosch, Norbert H.A. van den; Jarva, Hanna; Junnikkala, Sami; Meri, Seppo; Bos, Jan D.; Asghar, Syed S.

doi:10.1016/j.molimm.2005.02.009

Cited by 36 publications

(24 citation statements)

References 55 publications

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“…Since we showed that RPE cells show regulated expression of CFH in their cytoplasmic compartment, we next wanted to determine whether CFH was secreted, consistent with a previous finding that human keratinocytes released CFH into the culture medium [32]. To determine whether CFH was secreted into the serum-free RPE cell culture medium, CFH expression was examined in the cell-free supernatants of RPE cells with or without IFN-γ treatment using Western blot analysis.…”

Section: Resultsmentioning

confidence: 88%

Regulated secretion of complement factor H by RPE and its role in RPE migration

Kim

Kase

et al. 2009

Graefes Arch Clin Exp Ophthalmol

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Background Variants in the gene for complement factor H (CFH) have been implicated as a major risk factor for the development of age-related macular degeneration (AMD). Little is known, however, about the factors regulating local expression and secretion of CFH by retinal pigment epithelial cells (RPE). Methods Cultured human early passage RPE cells, highly differentiated, polarized human RPE cultures, and bovine RPE explants were incubated in the presence or absence of recombinant human or bovine interferon-γ (IFN-γ; 25 ng/ml). CFH expression in cell lysates, and secretion into culture supernatants were examined by Western blot. CHF expression and localization was analyzed by confocal microscopy. Migration assay was performed in a modified Boyden chamber with early passage human RPE cells after stimulation with recombinant CFH protein (1–100 ng/ml). Results CFH was expressed in the cell lysates of RPE cells, and this expression was significantly upregulated by IFN-γ. Immunoreactivity for CFH was detected in RPE cells of bovine explants and highly differentiated human RPE monolayers, and the level of immunoreactivity increased after IFN-γ stimulation. Confocal microscopy revealed that CFH was predominantly localized in the apical cytoplasm of polarized human RPE. Western blot confirmed that IFN-γ increased CFH secretion into RPE supernatants. Dose dependent RPE cell chemotactic migration was induced by CFH. Conclusion IFN-γ promotes CFH expression in the apical compartment of RPE cells and increases secretion of CFH into RPE culture supernatants. Furthermore, CFH promotes chemotactic migration of RPE. This study suggests that interactions between CFH and IFN-γ have the potential to play a role in the pathogenesis of AMD.

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Section: Resultsmentioning

confidence: 88%

Regulated secretion of complement factor H by RPE and its role in RPE migration

Kim

Kase

et al. 2009

Graefes Arch Clin Exp Ophthalmol

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“…Epidermal keratinocytes (KCs) constitutively secrete C3, factor B, and factor H and have been shown to release high amounts of C3 after stimulation with proinflammatory cytokines (22,23). Increased levels of C3a in the circulation have been found in diseases such as adult respiratory distress syndrome (24), asthma (25), psoriasis, and atopic dermatitis (AD) (26).…”

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confidence: 99%

Induction of C3 and CCL2 by C3a in Keratinocytes: A Novel Autocrine Amplification Loop of Inflammatory Skin Reactions

Purwar

Wittmann

Zwirner

et al. 2006

The Journal of Immunology

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The complement fragment-3a (C3a) acts via a G protein-coupled C3aR and is of importance in allergic and inflammatory diseases. Recent studies suggest the presence of complement proteins in the epidermal compartment and synthesis of some of these proteins (C3, factor B, and factor H) by human primary keratinocytes (KCs) during inflammation. However, expression of C3aR and its role in human KCs is not elucidated thus far. In this study, we demonstrate the expression of C3aR on KCs as detected by quantitative real-time RT-PCR and flow cytometry. IFN-γ and IFN-α strongly up-regulated the surface expression of C3aR on KCs among all other cytokines tested. After up-regulation of C3aR by IFN-γ and IFN-α, we observed the induction of five genes (CCL2, CCL5, CXCL8, CXCL10, and C3) after stimulation of KCs with C3a in microarray analysis. We confirmed the induction of C3 and CCL2 at RNA and protein levels. Furthermore, incubation of C3 with skin mast cells tryptase resulted in the generation of C3 fragments with C3a activity. In conclusion, our data illustrate that epidermal KCs express functional C3aR. The increases of C3 and CCL2 synthesis by C3a and C3 activation by skin mast cell tryptase delineates a novel amplification loop of complement activation and inflammatory responses that may influence the pathogenesis of allergic/inflammatory skin diseases.

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“…The normal concentration of fH in plasma ranges from 233 to 269 mg/ml in young and old individuals, respectively (43), although other studies suggest that the concentration of fH in plasma is 2-fold higher (44,45). The primary synthesis of fH occurs in the liver (16); however, other cell types can produce fH, including monocytes (46), endothelial cells (47), keratinocytes (48), and synovial cells (49). We also found that mice completely deficient in fH developed no arthritis and that these mice were resistant to CAIA, which is in contrast to the membranoproliferative glomerulonephritis type II in fH 2/2 mice and accelerated injury following the injection of subnephritogenic doses of antisera (29).…”

Section: Discussionmentioning

confidence: 99%

Essential Role of Surface-Bound Complement Factor H in Controlling Immune Complex–Induced Arthritis

Banda

Mehta

Ferreira

et al. 2013

The Journal of Immunology

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Factor H (fH) is an endogenous negative regulator of the alternative pathway (AP) that binds polyanions as well as complement activation fragments C3b and C3d. The AP is both necessary and sufficient to develop collagen Ab–induced arthritis (CAIA) in mice; the mechanisms whereby normal control of the AP is overcome and injury develops are unknown. Although primarily a soluble circulating protein, fH can also bind to tissues in a manner dependent on the carboxyl-terminal domain containing short consensus repeats 19 and 20. We examined the role of fH in CAIA by blocking its binding to tissues through administration of a recombinant negative inhibitor containing short consensus repeats 19 and 20 (rfH19-20), which impairs fH function and amplifies surface AP activation in vitro. Administration of rfH19-20, but not control rfH3-5, significantly worsened clinical disease activity, histopathologic injury, and C3 deposition in the synovium and cartilage in wild-type and fH+/− mice. In vitro studies demonstrated that rfH19-20 increased complement activation on cartilage extracts and injured fibroblast-like synoviocytes, two major targets of complement deposition in the joint. We conclude that endogenous fH makes a significant contribution to inhibition of the AP in CAIA through binding to sites of immune complex formation and complement activation.

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Human keratinocytes produce the complement inhibitor factor H: Synthesis is regulated by interferon-γ

Cited by 36 publications

References 55 publications

Regulated secretion of complement factor H by RPE and its role in RPE migration

Regulated secretion of complement factor H by RPE and its role in RPE migration

Induction of C3 and CCL2 by C3a in Keratinocytes: A Novel Autocrine Amplification Loop of Inflammatory Skin Reactions

Essential Role of Surface-Bound Complement Factor H in Controlling Immune Complex–Induced Arthritis

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