Lymphotoxin, Tumor Necrosis Factor, and Gamma Interferon Are Cytostatic for Normal Human Keratinocytes

Symington, Frank W.

doi:10.1111/1523-1747.ep12696816

Cited by 86 publications

(27 citation statements)

References 39 publications

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“…The lack of epidermal thickening we observed in IL-21-treated RAG1-deficient mice apparently conflicts with our previous demonstration that IL-21 is growth stimulatory for human keratinocytes in vitro (7). In this context, however, it is noteworthy that other studies have previously shown that keratinocytes can respond differently to recombinant cytokines in terms of proliferation and survival depending on whether they are stimulated in vitro or in vivo (19,20). CD4 + T cells cloned from psoriatic lesions stimulate keratinocyte growth in vitro through a mechanism, which is supposed to be largely mediated by Th1/Th17-related cytokines (3,21,22).…”

Section: Discussioncontrasting

confidence: 92%

“…These findings are consistent with results of previous studies showing that IFN-g administration in vivo to psoriatic uninvolved skin results in epidermal hyperproliferation (19). By contrast, IFN-g was reported to exert inhibitory effects on the growth of keratinocytes in vitro in primary cultures (20). A plausible explanation for these discrepancies is that IFN-g is critical but not sufficient to drive keratinocytes proliferation and that, in vivo in the epidermis, other factors provide the necessary costimulatory signals for IFN-g to become growth stimulatory.…”

Section: Discussionmentioning

confidence: 99%

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IL-21 Promotes Skin Recruitment of CD4+ Cells and Drives IFN-γ–Dependent Epidermal Hyperplasia

Sarra

Caruso

Cupi

et al. 2011

The Journal of Immunology

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Psoriasis is a chronic inflammatory disorder of the skin characterized by epidermal hyperplasia and infiltration of leukocytes into the dermis and epidermis. T cell-derived cytokines, such as IFN-γ and IL-17A, play a major role in the psoriasis-associated epidermal hyperplasia, even though factors/mechanisms that regulate the production of these cytokines are not fully understood. We have recently shown that IL-21 is synthesized in excess in psoriatic skin lesions and causes epidermal hyperplasia when injected intradermally in mice. Moreover, in the human psoriasis SCID mouse model, neutralization of IL-21 reduces both skin thickening and expression of inflammatory molecules, thus supporting the pathogenic role of IL-21 in psoriasis. However, the basic mechanism by which IL-21 promotes skin pathology remains unknown. In this study, we show that CD4+ cells accumulate early in the dermis of IL-21–treated mice and mediate the development of epidermal hyperplasia. Indeed, IL-21 fails to induce skin damage in RAG1-deficient mice and CD4+ cell-depleted wild-type mice. The majority of CD4+ cells infiltrating the dermis of IL-21–treated mice express IFN-γ and, to a lesser extent, IL-17A. Studies in cytokine knockout mice show that IFN-γ, but not IL-17A, is necessary for IL-21–induced epidermal hyperplasia. Finally, we demonstrate that IFN-γ–producing CD4+ cells infiltrating the human psoriatic plaque express IL-21R, and abrogation of IL-21 signals reduces IFN-γ expression in cultures of psoriatic CD4+ cells. Data indicate that IL-21 induces an IFN-γ–dependent pathogenic response in vivo, thus contributing to elucidate a mechanism by which IL-21 sustains skin-damaging inflammation.

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Section: Discussioncontrasting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

IL-21 Promotes Skin Recruitment of CD4+ Cells and Drives IFN-γ–Dependent Epidermal Hyperplasia

Sarra

Caruso

Cupi

et al. 2011

The Journal of Immunology

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“…Basal keratinocyte cell lines were prepared from neonatal foreskin and cultured in MCDB 153 serum-free medium with modifications as previously described using human recombinant epidermal growth factor prepared and generously provided by C. Georges-Nascimento, Chiron Corporation ( 18). Keratinocytes were used at second through fourth passage (2-4 wk of culture).…”

Section: Methodsmentioning

confidence: 99%

Herpes simplex virus infection of human fibroblasts and keratinocytes inhibits recognition by cloned CD8+ cytotoxic T lymphocytes.

Koelle¹,

Tigges²,

Burke³

et al. 1993

J. Clin. Invest.

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CD8' cytotoxic T lymphocytes (CTL) clones with specificity for herpes simplex virus (HSV) were derived from two donors with genital HSV-2 infection. These CIL clones specifically lysed HSV-infected autologous B lymphoblastoid cells, but not HSV-infected fibroblasts. Exogenous peptide loading sensitized both cell types to lysis by an HSV-specific ClL clone of known specificity. HSV infection rendered fibroblasts refractory to peptide sensitization. HSV infection also rendered fibroblasts and keratinocytes insensitive to lysis by allospecific CD8 + CI'L clones. Lysis of B lymphoblastoid cells in this system was only slightly reduced by HSV infection. Reduction of fibroblast allospecific lysis was dose and time dependent and was blocked by acyclovir, indicating the involvement of a late HSV gene product. HSV caused a reduction of fibroblast cell surface HLA class I antigen, at least in part due to reduction of synthesis of heavy chain-f32 microglobulin heterodimers. These results suggest that HSV-induced blockade ofantigen presentation by cutaneous cells to CD8+ CTL may be a mechanism by which HSV limits or evades the immune response of the host. (J. Clin. Invest. 1993. 91:961-968.)

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“…35 When cultured keratinocytes are treated with TNF-␣, proliferation is inhibited but differentiation is promoted. 37,38 TNF-␣ induces adhesion molecules and apoptosis of keratinocytes. 39 In our samples, the localization of MMP-19 did not histologically correlate with apoptosis.…”

Section: Northern and Western Analyses Of Keratinocytesmentioning

confidence: 99%

Matrix metalloproteinase‐19 is expressed by proliferating epithelium but disappears with neoplastic dedifferentiation

Impola

Toriseva

Suomela

et al. 2002

Intl Journal of Cancer

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Lymphotoxin, Tumor Necrosis Factor, and Gamma Interferon Are Cytostatic for Normal Human Keratinocytes

Cited by 86 publications

References 39 publications

IL-21 Promotes Skin Recruitment of CD4+ Cells and Drives IFN-γ–Dependent Epidermal Hyperplasia

IL-21 Promotes Skin Recruitment of CD4+ Cells and Drives IFN-γ–Dependent Epidermal Hyperplasia

Herpes simplex virus infection of human fibroblasts and keratinocytes inhibits recognition by cloned CD8+ cytotoxic T lymphocytes.

Matrix metalloproteinase‐19 is expressed by proliferating epithelium but disappears with neoplastic dedifferentiation

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