Inflammatory skin disease in transgenic mice that express high levels of interleukin 1 alpha in basal epidermis.

Groves, Richard; Mizutani, Hitoshi; Kieffer, J. David; Kupper, Thomas S.

doi:10.1073/pnas.92.25.11874

Cited by 188 publications

(173 citation statements)

References 28 publications

(16 reference statements)

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“…We have postulated previously that keratinocyte expression of IL-1R2 could be a mechanism by which IL-1-mediated cutaneous responses are negatively regulated (10,11). The data presented in this report represent the first in vivo evidence of inhibition of IL-1 inhibition mediated by IL-1R2 in cutaneous microenvironment, and indicates that this local inhibition can proceed without systemic antagonism of IL-1.…”

Section: Discussionsupporting

confidence: 55%

“…We have successfully targeted IL-1R2 to basal keratinocytes using a human keratin 14 promoter (11,12). Our results indicate that IL-1R2 expressed by keratinocytes in vivo can indeed inhibit IL-1-mediated inflammatory responses, both in epidermis and in dermis.…”

mentioning

confidence: 85%

“…[7][8][9][10]. It was recently shown that release of the primary cytokine IL-1␣ from basal keratinocytes in vivo is sufficient to both initiate and mediate cutaneous inflammation in vivo (11,12). Because active species of IL-1 mediate so many pathophysiological processes relevant to inflammation (13), molecular mechanisms that limit the degree and duration of IL-1 activity have evolved.…”

mentioning

confidence: 99%

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Keratinocyte expression of the type 2 interleukin 1 receptor mediates local and specific inhibition of interleukin 1-mediated inflammation

Rauschmayr

Groves

Kupper

1997

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

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Epidermal keratinocytes can express two types of interleukin 1 (IL-1) receptors: IL-1R1, which is active in signal transduction, and the less well characterized IL-1R2, which is incapable of transducing a signal and can be shed from cells. The binding of IL-1 in solution by IL-1R2 has been demonstrated, and it has been proposed to inhibit IL-1-mediated responses through this mechanism. We and others have reported that keratinocytes can be induced to express IL-1R2 both in vitro and in vivo, often under conditions that also favor IL-1 gene expression. We hypothesized that production of IL-1R2 by keratinocytes would be an efficient means to achieve local inhibition of IL-1-mediated responses without systemic consequences. To test this hypothesis, we have generated transgenic mice that constitutively express IL-1R2 on basal keratinocytes. Keratinocytes cultured from these animals shed the soluble form of the receptor into culture supernatants, and IL-1-inducible production of granulocyte͞macrophage colony-stimulating factor was markedly inhibited. In vivo, acute cutaneous vascular leakage, as well as chronic inf lammation induced by a well characterized IL-1-dependent stimulus, was significantly inhibited in IL-1R2 transgenic animals. In contrast, contact hypersensitivity was unaffected, suggesting that overexpression of IL-1R2 did not inhibit all types of inf lammation globally. Finally, systemic injection of IL-1 induced equivalent levels of plasma IL-6 in IL-1R2 transgenic and nontransgenic mice, suggesting that the activity of the transgenic IL-1R2 remained predominantly local and did not inf luence systemic IL-1 responses. We conclude that tissue-specific production of IL-1R2 can mediate IL-1 antagonism in tissue microenvironments without systemic consequences. Our transgenic mice may be a useful tool for determining the degree to which different types of cutaneous inf lammation depend on the IL-1 system.

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Section: Discussionsupporting

confidence: 55%

mentioning

confidence: 85%

mentioning

confidence: 99%

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Keratinocyte expression of the type 2 interleukin 1 receptor mediates local and specific inhibition of interleukin 1-mediated inflammation

Rauschmayr

Groves

Kupper

1997

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

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“…IL-1β has been shown to be expressed in the skin in vivo and in keratinocytes in 2D culture (48,49), where it may represent epidermal "activation" in response to epithelial injury and…”

Section: Discussionmentioning

confidence: 99%

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

Araya¹,

Cambier²,

Markovics³

et al. 2007

J. Clin. Invest.

230

228

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Squamous metaplasia (SM) is common in smokers and is associated with airway obstruction in chronic obstructive pulmonary disease (COPD). A major mechanism of airway obstruction in COPD is thickening of the small airway walls. We asked whether SM actively contributes to airway wall thickening through alteration of epithelial-mesenchymal interactions in COPD. Using immunohistochemical staining, airway morphometry, and fibroblast culture of lung samples from COPD patients; genome-wide analysis of an in vitro model of SM; and in vitro modeling of human airway epithelial-mesenchymal interactions, we provide evidence that SM, through the increased secretion of IL-1β, induces a fibrotic response in adjacent airway fibroblasts. We identify a pivotal role for integrin-mediated TGF-β activation in amplifying SM and driving IL-1β-dependent profibrotic mesenchymal responses. Finally, we show that SM correlates with increased severity of COPD and that fibroblast expression of the integrin α v β 8 , which is the major mediator of airway fibroblast TGF-β activation, correlated with disease severity and small airway wall thickening in COPD. Our findings have identified TGF-β as a potential therapeutic target for COPD.

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“…IL-1a predominates in keratinocytes, while IL-1b is the predominant form in monocytes, macrophages and dendritic cells. Transgenic overexpression of IL-1a by basal keratinocytes in mice results in hair loss, scaling, and focal inflammatory lesions (210).…”

Section: Uvb-mediated Cytokine Expression Primary Cytokines: Tnf-a Anmentioning

confidence: 99%

The pathophysiology of photosensitivity in lupus erythematosus

Orteu

Sontheimer

Dutz

2001

Photoderm Photoimm Photomed

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Inflammatory skin disease in transgenic mice that express high levels of interleukin 1 alpha in basal epidermis.

Cited by 188 publications

References 28 publications

Keratinocyte expression of the type 2 interleukin 1 receptor mediates local and specific inhibition of interleukin 1-mediated inflammation

Keratinocyte expression of the type 2 interleukin 1 receptor mediates local and specific inhibition of interleukin 1-mediated inflammation

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

The pathophysiology of photosensitivity in lupus erythematosus

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