Expression of cytokines and their receptors by psoriatic fibroblasts I. Altered IL-6 synthesis

Debets, Reno; Hegmans, Joost P.; Deleuran, Mette; Hooft, Sinka 't; Benner, R.; Prens, Errol P.

doi:10.1006/cyto.1996.0010

Cited by 22 publications

(13 citation statements)

References 56 publications

(43 reference statements)

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“…IL-6 and IL-8 were also elevated in the patient's serum (Supplemental Table 3). Elevation of IL-6 and IL-8 has been demonstrated in psoriatic skin and fibroblasts and is considered an amplifier of skin inflammation (21). The classical proinflammatory cytokine TNF-α was normal in the patient, consistent with the failure of the dermatitis to respond to treatment with TNF-α inhibitor etanercept.…”

Section: Figurementioning

confidence: 61%

Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay

He¹,

Kratz²,

Michel³

et al. 2011

J. Clin. Invest.

111

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Defects in cholesterol synthesis result in a wide variety of symptoms, from neonatal lethality to the relatively mild dysmorphic features and developmental delay found in individuals with Smith-Lemli-Opitz syndrome. We report here the identification of mutations in sterol-C4-methyl oxidase-like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay. This gene encodes a sterol-C4-methyl oxidase (SMO), which catalyzes demethylation of C4-methylsterols in the cholesterol synthesis pathway. C4-Methylsterols are meiosis-activating sterols (MASs). They exist at high concentrations in the testis and ovary and play roles in meiosis activation. In this study, we found that an accumulation of MASs in the patient led to cell overproliferation in both skin and blood. SMO deficiency also substantially altered immunocyte phenotype and in vitro function. MASs serve as ligands for liver X receptors α and β (LXRα and LXRβ), which are important in regulating not only lipid transport in the epidermis, but also innate and adaptive immunity. Deficiency of SMO represents a biochemical defect in the cholesterol synthesis pathway, the clinical spectrum of which remains to be defined. IntroductionCholesterol is a key component of cell membranes and lipid rafts and is the immediate precursor of steroids, vitamin D, and bile acids. Many disorders of cholesterol synthesis share common clinical features, such as abnormal morphogenesis, growth delay, and psychomotor disabilities (1). However, there are also striking differences suggesting that reduced de novo cholesterol synthesis per se may not primarily underlie some of the symptoms, including cataracts as well as skin and immune system abnormalities. Rather, recent studies implicate the accumulation of pre-cholesterol sterols and the replacement of cholesterol with some of these sterols in lipid rafts as playing a key role in the underlying pathophysiology (2). The meiosis-activating sterols (MASs) were the first group of cholesterol biogenesis intermediates that were found to have important extrahepatic functions in mammals. These include 4,4′-dimethyl-5α-cholesta-8,24-dien-3β-ol (testis meiosis-activating sterol [T-MAS]), 4,4′-dimethyl-5α-cholesta-8,14,24-trien-3β-ol (follicular fluid meiosis-activating sterols [FF-MASs]), and zymosterol. They are found in high concentration in testis and ovary and play roles in oocyte maturation and meiosis activation. The function of the MASs outside the reproductive organs is not well studied. FF-MAS is also a ligand for liver X receptors (LXRs) (3). LXR signaling is known to regulate crosstalk between inflammatory and cholesterol metabolism,

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Section: Figurementioning

confidence: 61%

Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay

He¹,

Kratz²,

Michel³

et al. 2011

J. Clin. Invest.

111

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“…There were, however, prominent HLA-DR findings in tbe dermis, presumably identifying dermal macrophages and dendritic cells (32) and supporting the conclusion that the source of the cytokines in the microdialysates was predominately dermal. Which cells within the dermis are actually producing the cytokines in this study is as yet unclear, but several types of tissue cells are known to produce and store pro-inflammatory cytokines (33)(34)(35). The combination of microdialysis with end-point tissue biopsy gives complementary information in the experimental setting and is likely to be of further use in studies of diseased skin in which the number of cells in the dermis is greater.…”

Section: Discussionmentioning

confidence: 96%

Sterile Trauma to Normal Human Dermis Invariably Induces IL1beta, IL6 and IL8 in an Innate Response to “Danger”

Sjögren¹,

Anderson²

2009

Acta Derm Venerol

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Microdialysis allows the study of the local production and temporal resolution of cytokines in living skin. Samples were taken from the normal skin of 10 healthy subjects for 24-28 h after insertion of a concentric microdialysis catheter, and analysed with a Luminex bead-based assay. Interleukin-1 beta (IL1b), IL6 and IL8 were seen in all subjects at all time-points after the first hour. Levels peaked at 5-8 h, equilibrating to lower levels at 24 h. Immunohistological double staining for human leukocyte antigen (HLA)-DR and intracellular cytokines on biopsies taken after catheter removal showed many stained cells in the dermis, in contrast to the few cells stained in the epidermis. This study demonstrates the reactive capability of the dermis when provoked separately from the epidermis. The production of IL1b, IL6 and IL8 occurs invariably in what can be termed an innate, dermal response to "danger"; in this case in the form of sterile needle trauma.

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“…IL-6 is produced by numerous cell types, including macrophages, monocytes, fibroblasts, endothelial cells, and smooth muscle cells. In vivo studies have shown low levels of constitutive IL-6 production by fibroblasts of different origins, including dermal (5), liver (myo) (24), duodenal (22), renal (15), foreskin (14), human periodontal ligament (20,27), oral fibrotic submucosal and buccal mucosal (3), and normal human gingival (3,11,12,19) origins.…”

mentioning

confidence: 99%

Effect of Lipopolysaccharide and Inflammatory Cytokines on Interleukin-6 Production by Healthy Human Gingival Fibroblasts

Kent

Rahemtulla²,

Hockett³

et al. 1998

Infect Immun

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Cytokines are hormone-like proteins which mediate and regulate inflammatory and immune responses. The purpose of this study was to investigate the effect of lipopolysaccharide (LPS) and inflammatory cytokines on regulation of interleukin-6 (IL-6) production by human gingival fibroblasts (HGF). The HGF cell lines used in this study, H-CL and F-CL, were established by the explant technique from healthy gingival tissue. Cultured cells were grown to confluency and incubated with various concentrations of LPS from Escherichia coli orPorphyromonas gingivalis or with the recombinant human cytokine tumor necrosis factor alpha (TNF-α), IL-1α, or IL-1β. Culture supernatants were collected at various times and assessed for IL-6 production by enzyme-linked immunosorbent assay. Total RNA was isolated from the harvested cells and used to assess levels of IL-6 mRNA by the RNase protection assay. Both LPS preparations induced IL-6 production (1 to 4 ng of IL-6 per ml) by both HGF cell lines. Although TNF-α stimulated IL-6 production by HGF, >10-fold-larger amounts were induced with IL-1α and IL-1β. Furthermore, the addition of both IL-1α and TNF-α to cultured cells resulted in approximately 600- to 800-fold-higher levels of IL-6 than seen in control cultures, suggesting that these cytokines synergistically induced IL-6 production by HGF. IL-6 message in cultured cells was upregulated 20-fold by TNF-α, 1,000-fold by IL-1α and IL-1β, and 1,400-fold by IL-1α plus TNF-α. IL-1α and TNF-α alone upregulate IL-6 production in a dose- and time-dependent fashion. The addition of IL-1α and TNF-α to cultured HGF cells resulted in a synergistic induction of IL-6 after 8 h of incubation and when greater than 10 pg of this combination per ml was used. Our studies show that inflammatory cytokines are hundreds of times more potent than LPS in stimulating IL-6 production by HGF.

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Expression of cytokines and their receptors by psoriatic fibroblasts I. Altered IL-6 synthesis

Cited by 22 publications

References 56 publications

Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay

Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay

Sterile Trauma to Normal Human Dermis Invariably Induces IL1beta, IL6 and IL8 in an Innate Response to “Danger”

Effect of Lipopolysaccharide and Inflammatory Cytokines on Interleukin-6 Production by Healthy Human Gingival Fibroblasts

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