GM-CSF Activates Regenerative Epidermal Growth and Stimulates Keratinocyte Proliferation in Human Skin In Vivo

Braunstein, Scott; Kaplan, Gilla; Gottlieb, Alice B.; Schwartz, Melanie; Walsh, G. P.; Abalos, Rodolfo M.; Fajardo, T. T.; Guido, L. S.; Krueger, James G.

doi:10.1111/1523-1747.ep12396936

Cited by 98 publications

(88 citation statements)

References 20 publications

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“…Although there are no data available concerning the effects of GM-CSF during lung injury, in the skin, GM-CSF is mitogenic for keratinocytes. Injection of recombinant GM-CSF into the dermal lesions of patients with leprosy induces keratinocyte proliferation and regenerative differentiation (47). Type II alveolar epithelial cells function as stem cells for the alveolar epithelium, proliferating and subsequently differentiating to replace thin type I alveolar cells that are particularly susceptible to injury (48).…”

Section: Discussionmentioning

confidence: 99%

Granulocyte-Macrophage Colony-Stimulating Factor in the Innate Immune Response toPneumocystis cariniiPneumonia in Mice

Paine

Preston

Wilcoxen

et al. 2000

The Journal of Immunology

141

111

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Innate immunity plays an important role in pulmonary host defense against Pneumocystis carinii, an important pathogen in individuals with impaired cell-mediated immunity. We investigated the role of GM-CSF in host defense in a model of P. carinii pneumonia induced by intratracheal inoculation of CD4-depleted mice. Lung GM-CSF levels increased progressively during the infection and were significantly greater than those in uninfected controls 3, 4, and 5 wk after inoculation. When GM-CSF gene-targeted mice (GM ؊/؊ ) depleted of CD4 ؉ cells were inoculated with P. carinii, the intensities of infection and inflammation were increased significantly compared with those in CD4-depleted wild-type mice. In contrast, transgenic expression of GM-CSF directed solely in the lungs of GM ؊/؊ mice (using the surfactant protein C promoter) dramatically decreased the intensity of infection and inflammation 4 wk after inoculation. The concentrations of surfactant proteins A and D were greater in both uninfected and infected GM ؊/؊ mice compared with those in wild-type controls, suggesting that this component of the innate response was preserved in the GM ؊/؊ mice. However, alveolar macrophages (AM) from GM ؊/؊ mice demonstrated impaired phagocytosis of purified murine P. carinii organisms in vitro compared with AM from wild-type mice. Similarly, AM production of TNF-␣ in response to P. carinii in vitro was totally absent in AM from GM ؊/؊ mice, while GM-CSF-replete mice produced abundant TNF in this setting. Thus, GM-CSF plays a critical role in the inflammatory response to P. carinii in the setting of impaired cell-mediated immunity through effects on AM activation.

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Section: Discussionmentioning

confidence: 99%

Granulocyte-Macrophage Colony-Stimulating Factor in the Innate Immune Response toPneumocystis cariniiPneumonia in Mice

Paine

Preston

Wilcoxen

et al. 2000

The Journal of Immunology

141

111

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“…52 Whereas GM-CSF is only minimally, if at all, expressed in normal skin and is not found in unstimulated keratinocyte cultures, 23 increased expression has been shown in many skin diseases, and it is readily induced in a paracrine fashion by cytokines, including interleukin (IL)-1, IL-2, TGF-␣, and TNF-␣. 53 Direct intradermal injection of GM-CSF into human skin causes keratinocyte enlargement and thickening of the epidermis.…”

Section: Discussionmentioning

confidence: 99%

Arsenic Enhancement of Skin Neoplasia by Chronic Stimulation of Growth Factors

Germolec

Spalding

Yu³

et al. 1998

The American Journal of Pathology

187

118

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Although numerous epidemiological studies have shown that inorganic arsenicals cause skin cancers and hyperkeratoses in humans , there are currently no established mechanisms for their action or animal models. Previous studies in our laboratory using primary human keratinocyte cultures demonstrated that micromolar concentrations of inorganic arsenite increased cell proliferation via the production of keratinocyte-derived growth factors. As recent reports demonstrate that overexpression of keratinocyte-derived growth factors , such as transforming growth factor (TGF)-␣, promote the formation of skin tumors , we hypothesized that similar events may be responsible for those associated with arsenic skin diseases. Thus , the influence of arsenic in humans with arsenic skin disease and on mouse skin tumor development in transgenic mice was studied. After low-dose application of tetradecanoyl phorbol acetate (TPA) , a marked increase in the number of skin papillomas occurred in Tg.AC mice , which carry the v-Haras oncogene , that received arsenic in the drinking water as compared with control drinking water, whereas no papillomas developed in arsenic-treated transgenic mice that did not receive TPA or arsenic/ TPA-treated wild-type FVB/N mice. Consistent with earlier in vitro findings , increases in granulocyte/ macrophage colony-stimulating factor (GM-CSF) and TGF-␣ mRNA transcripts were found in the epidermis at clinically normal sites within 10 weeks after arsenic treatment. Immunohistochemical staining localized TGF-␣ overexpression to the hair follicles. Injection of neutralizing antibodies to GM-CSF after TPA application reduced the number of papillomas in Tg.AC mice. Analysis of gene expression in samples of skin lesions obtained from humans chronically exposed to arsenic via their drinking water also showed similar alterations in growth factor expression. Although confirmation will be required in nontransgenic mice, these results suggest that arsenic enhances development of skin neoplasias via the chronic stimulation of keratinocyte-derived growth factors and may be a rare example of a chemical carcinogen that acts as a co-promoter. (Am J Pathol 1998, 153:1775-1785) Arsenic, a ubiquitous element, represents a human health concern when concentrated in the environment from natural or anthropogenic processes. Arsenic contamination of water supplies has resulted in a very high incidence of skin lesions and cancers in exposed populations from Taiwan, China, Eastern Europe, India, Southwestern United States, and Cental and South America. The U.S. Environmental Protection Agency (EPA) estimates that over 350,000 people in the U.S. consume drinking water containing over 50 g/L arsenic, the current EPA standard, 1 and there is significant regulatory pressure to lower the acceptable levels. Chronic exposure to inorganic arsenic in drinking water is most often associated with increased mortality from skin cancer, but recent studies have also linked arsenic exposure to neoplasias in internal organs, including the lung, liv...

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“…In this way, increased concentrations of GM-CSF at the skin level could explain the persistent infiltration of monocytes and activated DC. Finally, GM-CSF is to date the only cytokine that has been shown to be mitogenic for human keratinocytes, both in vivo (43,46) and in vitro (47), thus representing a favored autocrine factor responsible for the epidermal hyperplasia observed in chronic AD.…”

Section: Discussionmentioning

confidence: 99%

Granulocyte macrophage colony-stimulating factor is overproduced by keratinocytes in atopic dermatitis. Implications for sustained dendritic cell activation in the skin.

et al. 1997

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Lesional skin of atopic dermatitis (AD) harbors high numbers of dendritic cells with enhanced stimulatory capacity for T lymphocytes. In this study, lesional AD skin was shown to stain heavily in both epidermal and dermal compartments for GM-CSF, a cytokine crucial to dendritic cell functions. Keratinocyte cultures established from uninvolved skin of AD patients exhibited markedly increased spontaneous and PMA-stimulated release of GM-CSF compared with keratinocytes from nonatopic controls. Correspondingly, keratinocytes from AD patients showed higher constitutive as well as PMA-induced GM-CSF gene expression. Larger amounts of GM-CSF were produced by AD keratinocytes, also in response to IL-1 ␣ , but not after stimulation with LPS, lipoteichoic acid, or staphylococcal enterotoxin B. Hydrocortisone reduced GM-CSF gene expression and protein release in both atopic and control keratinocytes. Supernatants from atopic keratinocytes were able to strongly stimulate PBMC proliferation in a GM-CSF-dependent manner. Moreover, conditioned medium from PMA-treated AD keratinocytes, together with exogenous IL-4, could support phenotypical and functional maturation of peripheral blood precursors into dendritic cells. Enhanced production of GM-CSF by keratinocytes may contribute relevantly to the establishment and chronicity of AD lesions, in particular to the increased number, sustained activation, and enhanced antigen-presenting functions of dendritic cells. ( J. Clin. Invest. 1997. 99:3009-3017.)

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GM-CSF Activates Regenerative Epidermal Growth and Stimulates Keratinocyte Proliferation in Human Skin In Vivo

Cited by 98 publications

References 20 publications

Granulocyte-Macrophage Colony-Stimulating Factor in the Innate Immune Response toPneumocystis cariniiPneumonia in Mice

Granulocyte-Macrophage Colony-Stimulating Factor in the Innate Immune Response toPneumocystis cariniiPneumonia in Mice

Arsenic Enhancement of Skin Neoplasia by Chronic Stimulation of Growth Factors

Granulocyte macrophage colony-stimulating factor is overproduced by keratinocytes in atopic dermatitis. Implications for sustained dendritic cell activation in the skin.

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