Binding and biological effects of tumor necrosis factor alpha on cultured human neonatal foreskin keratinocytes.

Pillai, Sreekumar; Bikle, D. B.; Eessalu, Thomas E.; Aggarwal, Bharat B.; Elias, Peter M.

doi:10.1172/jci113963

Cited by 89 publications

(60 citation statements)

References 34 publications

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“…We have previously shown that tumors in K5-I B␣ mice do not display mutations in Ha-Ras (16), and we now find that there is no increase in activated MAPK in the skin or tumors of K5-I B␣ mice, essentially ruling out Ras as a factor critical to cancer development in this model. Interestingly, both Ras and Tnf␣ induce growth arrest in keratinocytes in vitro (4,21), and an attractive possibility is that keratinocytes with blocked NF-B signaling have lost the growth arrest response to both Ras and cytokines.…”

Section: Discussionmentioning

confidence: 99%

Tumor necrosis factor receptor 1-mediated signaling is required for skin cancer development induced by NF-κB inhibition

Lind

Rozell²,

Wallin³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

107

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T he Rel͞NF-B transcription factors have a central role in several cellular processes, including proliferation, cell adhesion, apoptosis, and regulation of the immune response (1). Under nonstimulating conditions, NF-B is retained in the cytoplasm in an inactive form because of its interaction with the inhibitory proteins I Bs. In response to an activating stimulus, I B is phosphorylated by an I B kinase (IKK) complex, which targets it for degradation by the proteasome, releasing NF-B, which translocates to the nucleus, where it regulates the transcription of target genes.Evidence gathered from studies during recent years have shown that NF-B has a growth inhibitory function in the skin. Initial studies showed that overexpression of the NF-B subunits p50 or p65 in the basal layer of the murine epidermis by using a keratin 14 (K14) promoter leads to hypoplasia of the epidermis, whereas expression of a superrepressor form of the inhibitor of NF-B type ␣ (I B␣) results in hyperplasia (2). Although K14-I B␣ mice die shortly after birth (day 7), we have shown that mice with keratin 5 (K5)-directed expression of I B␣ (K5-I B␣) to the basal layer of the epidermis survive to adulthood (3). Not only do these mice develop hyperplasia of the epidermis, but the skin phenotype of K5-I B␣ mice is also characterized by an intense neutrophil-dominated inflammation of the skin and an early development of squamous cell carcinomas (SCC).Recent data suggest that human sporadic SCC may show a block in NF-B signaling based on nuclear exclusion of the RelA NF-B subunit (ref. 4 and M.v.H., unpublished results). Furthermore, it was recently shown that coexpression of a superrepressor form of I B␣ and Ha-Ras results in neoplasia resembling invasive SCC in human keratinocytes transplanted to severe combined immunodeficient (scid͞scid) mice, supporting the relevance of a NF-B block in the induction of human SCC (4).Inflammation of the skin with neutrophil infiltration and hyperproliferation is also seen in female heterozygous Ikk␥-deficient mice, which develop a condition similar to the human X-linked disorder Incontinentia Pigmenti (IP) (5, 6). IKK␥ is the regulatory subunit of the IKK complex, which, in addition, contains the two catalytic subunits IKK␣ (IKK1) and IKK␤ (IKK2) (1). It is now well established that human IP results from loss-of-function mutations in the IKK␥ gene (7). Interestingly, subungual keratoacanthoma-like tumors and cases of SCC have been reported as late manifestations of IP (8-11).The catalytic IKK␤ subunit is necessary for activation of NF-B in response to proinflammatory stimuli (1). Skin-specific deletion of the IKK␤ gene, K14-Cre͞Ikk2 FL/FL , was recently shown to result in an inflammatory phenotype with concomitant hyperproliferation of the epidermis (12), very similar to what is seen in the K5-I B␣ mice. Because the K14-Cre͞Ikk2 FL/FL mice die between day 7 and day 9 after birth, it is currently not known whether they, similar to K5-I B␣ mice, are prone to develop SCC.Besides inf lammation and hyperprolifera...

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Section: Discussionmentioning

confidence: 99%

Tumor necrosis factor receptor 1-mediated signaling is required for skin cancer development induced by NF-κB inhibition

Lind

Rozell²,

Wallin³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

107

View full text Add to dashboard Cite

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“…Intradermal psoriatic graft treatments with IL-1 or IL-6 did not further enhance epidermal proliferation, probably because a saturating effect had already been reached. TNF-inhibits proliferation of human keratinocytes in culture [34], and several investigators have indicated a possible therapeutic effect of TNFin psoriasis [7][8][9]. Moreover, injection of TNF into mice inhibits keratinocyte proliferation [35].…”

Section: Discussionmentioning

confidence: 99%

In vivo effects of cytokines on psoriatic skin grafted on nude mice: involvement of the tumour necrosis factor (TNF) receptor

Gilhar

David

Kalish³

et al. 1996

Clinical and Experimental Immunology

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SUMMARYFollowing engraftment of human involved psoriatic skin to nude mice there is a partial normalization of pathology associated with a loss of inflammatory leucocytes. However, the epidermis remains hyperproliferative, which may reflect a primary defect. The roles of TNF-®, IL-1 and IL-6 in epidermal hyperproliferation of grafted psoriatic lesions were investigated. Before and after treatment, grafts were analysed to determine epidermal thickness and labelling index (LI). HLA-DR, intercellular adhesion molecule-1 (ICAM-1), and TNF receptor (TNF-R; p75 and p55) expression were determined by immunoperoxidase staining. Psoriatic epidermis was found consistently to be negative for p55 TNF-R and p75 TNF-R before grafting. Following engraftment, TNF-R-positive cells (i.e. p55 by keratinocytes; p75 by epidermal dendritic cells) were identified throughout the epidermis. Higher numbers of p75 TNF-R epidermal dendritic cells were found in grafts following a course of TNF-®, IL-6 or IL-1 treatment. The p55 form of the TNF-R expressed by keratinocytes was significantly elevated after treatment with TNF-® or IL-6. HLA-DR and ICAM-1 were also expressed in these grafts. TNF-®, anti-IL-1, and anti-IL-6 treatment induced a marked decrease in the epidermal thickness and LI of psoriatic graft tissue, correcting the hyperproliferation associated with psoriatic epidermis. Supraphysiological levels of TNF-® may saturate and consequently down-regulate their own receptors, leading to a paradoxical inhibitory effect.

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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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Binding and biological effects of tumor necrosis factor alpha on cultured human neonatal foreskin keratinocytes.

Cited by 89 publications

References 34 publications

Tumor necrosis factor receptor 1-mediated signaling is required for skin cancer development induced by NF-κB inhibition

Tumor necrosis factor receptor 1-mediated signaling is required for skin cancer development induced by NF-κB inhibition

In vivo effects of cytokines on psoriatic skin grafted on nude mice: involvement of the tumour necrosis factor (TNF) receptor

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

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