INTERFERON-γ INDUCES BIOSYNTHESIS OF COMPLEMENT COMPONENTS C2, C4 AND FACTOR H BY HUMAN PROXIMAL TUBULAR EPITHELIAL CELLS

Js, Gerritsma; Af, Gerritsen; M, De Ley; La, van Es; Mr, Daha

doi:10.1006/cyto.1996.0164

Cited by 61 publications

(43 citation statements)

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“…A previous study has shown mRNA and protein for CFH in the RPE, which populates the inner surface of Bruch's membrane, and several other tissues in the eye (25). In this study, we have confirmed that RPE cells produce CFH, and as is the case in human proximal tubular epithelial cells (41), expression of CFH in RPE cells is strongly stimulated by the inflammatory cytokine, IFN-␥. We have identified a relationship between the two major risk factors for AMD, because oxidative stress reduces IFN-␥-induced expression of CFH in RPE cells.…”

Section: Discussionsupporting

confidence: 84%

Oxidative Stress Modulates Complement Factor H Expression in Retinal Pigmented Epithelial Cells by Acetylation of FOXO3

Lauer

Sick

et al. 2007

Journal of Biological Chemistry

109

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Age-related macular degeneration (AMD), the leading cause of severe vision loss in the elderly, is a complex disease that results from genetic modifications that increase susceptibility to environmental exposures. Smoking, a major source of oxidative stress, increases the incidence and severity of AMD, and antioxidants slow progression, suggesting that oxidative stress plays a major role. Polymorphisms in the complement factor H (CFH) gene that reduce activity of CFH increase the risk of AMD. In this study we demonstrate an interaction between these two risk factors, because oxidative stress reduces the ability of an inflammatory cytokine, interferon-␥, to increase CFH expression in retinal pigmented epithelial cells. The interferon-␥-induced increase in CFH is mediated by transcriptional activation by STAT1, and its suppression by oxidative stress is mediated by acetylation of FOXO3, which enhances FOXO3 binding to the CFH promoter, reduces its binding to STAT1, inhibits STAT1 interaction with the CFH promoter, and reduces expression of CFH. Expression of SIRT1, a mammalian homolog of NAD-dependent protein deacetylase sir2, attenuated FOXO3 recruitment to the CFH regulatory region and reversed the H 2 O 2 -induced repression of CFH gene expression. These data suggest an important interaction between environmental exposure and genetic susceptibility in the pathogenesis of AMD and, by elucidating molecular signaling involved in the interaction, provide potential targets for therapeutic intervention.

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Section: Discussionsupporting

confidence: 84%

Oxidative Stress Modulates Complement Factor H Expression in Retinal Pigmented Epithelial Cells by Acetylation of FOXO3

Lauer

Sick

et al. 2007

Journal of Biological Chemistry

109

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“…Low production of C4 is unlikely to have been a limiting factor, because there was marked up-regulation of C4 mRNA localized to the tubular epithelium in rejecting grafts, and proximal tubule cells are known to efficiently translate and secrete expressed C4. 27,28 Although several mouse strains are reported to have low generation of C4 as a result of posttranscriptional regulation, 29 all our comparisons used a C4-high strain (B6) against C4 knockout mice. Thus, comparison was between high and absent C4 in the donor or recipient arrangements used.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of C4 from Donor or Recipient Mouse Fails to Prevent Renal Allograft Rejection

Lin

Zhou

Farrar

et al. 2006

The American Journal of Pathology

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Complement effector products generated in the transplanted kidney are known to mediate transplant rejection, but which of the three main activation pathways of complement trigger this response is unclear. Here we assessed the role of the classical and lectin pathways by studying the common component C4 in mouse kidney transplant rejection. We transplanted wild-type or C4-null H-2 b donor kidneys into H-2 k or H-2 d recipients, or vice-versa, to assess the roles of donor kidney and recipient expression of complement. Intragraft C4 gene expression rose substantially during rejection. However, we found no significant association between graft acceptance and the presence of C4 in either the donor kidney or recipient mouse. At the time of rejection, we found no significant differences in alloantibody response in the different groups. Tubular deposition of C3 to C9 occurred regardless of the absence or presence of C4 in either the donor or recipient mouse, indicating that C4 was dispensable for complement activation at this site. These data suggest that complement activation and renal allograft rejection are independent of the classical and lectin pathways in these models, implying that in the absence of these pathways the alternative pathway is the main trigger for complementmediated rejection.

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“…Multiple studies have demonstrated that inflammatory cytokines, such as tumor necrosis factor alpha, IL-1, IL-6, and gamma interferon, can induce increased production of complement from several cell types (19). It has previously been demonstrated that LPS stimulation in the absence of IL-10 results in marked increases in inflammatory cytokine production (e.g., tumor necrosis factor alpha, IL-1, IL-6, and gamma interferon) (4), and we hypothesize that increased inflammatory cytokine production in IL-10-deficient mice may contribute to an increase in the levels of complement in serum.…”

Section: Discussionmentioning

confidence: 99%

Role for Complement in Development ofHelicobacter-Induced Gastritis in Interleukin-10-Deficient Mice

Ismail¹,

Zhang²,

Lynch

et al. 2003

Infect Immun

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The mechanisms by which the immune response can eradicate gastric Helicobacter infection are unknown. We hypothesized that Helicobacter-induced activation of the complement system could promote both inflammation and eradication of Helicobacter from the stomach. In vitro studies demonstrated that Helicobacter felis activates complement in normal mouse serum but not in serum from Rag2 ؊/؊ mice, indicating that H. felis activates complement through the classical pathway. Next, we infected complement-depleted wild-type control and interleukin-10-deficient (IL-10 ؊/؊ ) mice with H. felis. Helicobacter infection of wild-type mice elicited a mild, focal gastritis and did not alter serum complement levels. Infection of IL-10 ؊/؊ mice with H. felis elicited severe gastritis. After the initial colonization, the IL-10 ؊/؊ mice completely cleared Helicobacter from the stomach by day 8. In contrast to wild-type mice, H. felis-infected IL-10 ؊/؊ mice had a marked increase in serum complement levels. Complement depletion of wild-type mice did not affect the intensity of gastric inflammation or the extent of Helicobacter colonization compared to that for the wild-type control mice. In contrast, complement depletion of Helicobacter-infected IL-10 ؊/؊ mice decreased the severity of gastritis, decreased the Helicobacter-induced infiltration of neutrophils into the stomach, and delayed the clearance of bacteria. In vitro studies of stimulated splenocytes and neutrophils from IL-10 ؊/؊ mice produced a twofold increase in complement production compared to that for wild-type mice. Pretreatment with IL-10 inhibited this increase. These studies identify a role for complement in the local immune response to gastric Helicobacter in IL-10 ؊/؊ mice and suggest a role for IL-10 in the regulation of complement production.

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INTERFERON-γ INDUCES BIOSYNTHESIS OF COMPLEMENT COMPONENTS C2, C4 AND FACTOR H BY HUMAN PROXIMAL TUBULAR EPITHELIAL CELLS

Cited by 61 publications

References 0 publications

Oxidative Stress Modulates Complement Factor H Expression in Retinal Pigmented Epithelial Cells by Acetylation of FOXO3

Oxidative Stress Modulates Complement Factor H Expression in Retinal Pigmented Epithelial Cells by Acetylation of FOXO3

Deficiency of C4 from Donor or Recipient Mouse Fails to Prevent Renal Allograft Rejection

Role for Complement in Development ofHelicobacter-Induced Gastritis in Interleukin-10-Deficient Mice

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