Cell Interaction and Epithelial Differentiation

Maas‐Szabowski, Nicole; Stark, Hans‐Jürgen; Fusenig, Norbert E.

doi:10.1002/0471221201.ch2

Cited by 24 publications

(26 citation statements)

References 77 publications

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“…One of such communications is the IL-1/ keratinocyte growth factor/granulocyte macrophage-colony stimulating factor double paracrine mechanism (37). Given the pivotal role of TAK1 in propagating the effect of numerous inflammatory cytokines, such as TNF-␣, the PDGF/HGF mechanism described herein complements the IL-1/keratinocyte growth factor/granulocyte macrophage-colony stimulating factor mechanism, particularly during wound repair.…”

Section: Discussionmentioning

confidence: 94%

Regulation of Cell Proliferation and Migration by TAK1 via Transcriptional Control of von Hippel-Lindau Tumor Suppressor

Tan

Pal

Tan

et al. 2009

Journal of Biological Chemistry

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Skin maintenance and healing after wounding requires complex epithelial-mesenchymal interactions purportedly mediated by growth factors and cytokines. We show here that, for wound healing, transforming growth factor-␤-activated kinase 1 (TAK1) in keratinocytes activates von Hippel-Lindau tumor suppressor expression, which in turn represses the expression of platelet-derived growth factor-B (PDGF-B), integrin ␤1, and integrin ␤5 via inhibition of the Sp1-mediated signaling pathway in the keratinocytes. The reduced production of PDGF-B leads to a paracrine-decreased expression of hepatocyte growth factor in the underlying fibroblasts. This TAK1 regulation of the double paracrine PDGF/hepatocyte growth factor signaling can regulate keratinocyte cell proliferation and is required for proper wound healing. Strikingly, TAK1 deficiency enhances cell migration. TAK1-deficient keratinocytes displayed lamellipodia formation with distinct microspike protrusion, associated with an elevated expression of integrins ␤1 and ␤5 and sustained activation of cdc42, Rac1, and RhoA. Our findings provide evidence for a novel homeostatic control of keratinocyte proliferation and migration mediated via TAK1 regulation of von Hippel-Lindau tumor suppressor. Dysfunctional regulation of TAK1 may contribute to the pathology of non-healing chronic inflammatory wounds and psoriasis.Wound healing is a highly dynamic process that involves complex interactions of extracellular matrix molecules, soluble mediators, various resident cells, and infiltrating leukocyte subtypes. The immediate goal in repair is to achieve tissue integrity and homeostasis. The healing process involves three phases that overlap in time and space, namely inflammation, re-epithelialization, and tissue remodeling. Re-epithelialization is accomplished by increased keratinocyte proliferation and guided migration of the keratinocytes over the granulation tissue. Such processes require ordered changes in keratinocyte behavior and phenotype, which are dictated by the interplay of keratinocytes with dermal fibroblasts, i.e. epithelial-mesenchymal communication. This complex interplay demands the integration of diverse signals through a network of soluble factors exerting autocrine and paracrine activity from the wound microenvironment, culminating in appropriate cellular responses (1, 2). Aberrations to this signaling network may impair or enhance cell migration and proliferation, leading to insufficient or excessive wound repair and life-threatening consequences such as tumor growth and metastasis. Therefore, to understand the effect of any molecule in normal cellular function, studies into its role in this signaling network and how they culminate to an appropriate cell response become fundamental and necessary.Transforming growth factor-␤ (TGF-␤) 4 -activated kinase 1 (TAK1) belongs to the MAPK kinase kinase family. This serine/ threonine kinase is a key intermediate in inflammatory cytokines tumor necrosis factor-␣ (TNF-␣) and interleukin 1 (IL-1) (3, 4) as well as TGF-␤ (5)-m...

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Section: Discussionmentioning

confidence: 94%

Regulation of Cell Proliferation and Migration by TAK1 via Transcriptional Control of von Hippel-Lindau Tumor Suppressor

Tan

Pal

Tan

et al. 2009

Journal of Biological Chemistry

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“…The absence of an UV-induced upregulation of CXCL5 in keratinocytes was unexpected because UV radiation is normally a potent inducer of several pro-inflammatory cytokines in human keratinocytes (10). As epidermal-dermal interactions play an important role in regulating skin homeostasis (11) and other studies demonstrated the importance of fibroblast-derived soluble factors for the regulation of epidermal homeostasis (12), we were interested in investigating the impact of keratinocyte-fibroblast interactions on expression and secretion of CXCL5 after UV exposure. Therefore, we used human three-dimensional organotypic skin cultures as a coculture model for keratinocytes and fibroblasts.…”

Section: Resultsmentioning

confidence: 99%

UV radiation induces CXCL5 expression in human skin

Reichert

Kolbe

Terstegen

et al. 2015

Experimental Dermatology

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CXCL5 has recently been identified as a mediator of UVB‐induced pain in rodents. To compare and to extend previous knowledge of cutaneous CXCL5 regulation, we performed a comprehensive study on the effects of UV radiation on CXCL5 regulation in human skin. Our results show a dose‐dependent increase in CXCL5 protein in human skin after UV radiation. CXCL5 can be released by different cell types in the skin. We presumed that, in addition to immune cells, non‐immune skin cells also contribute to UV‐induced increase in CXCL5 protein. Analysis of monocultured dermal fibroblasts and keratinocytes revealed that only fibroblasts but not keratinocytes displayed up regulated CXCL5 levels after UV stimulation. Whereas UV treatment of human skin equivalents, induced epidermal CXCL5 mRNA and protein expression. Up regulation of epidermal CXCL5 was independent of keratinocyte differentiation and keratinocyte‐keratinocyte interactions in epidermal layers. Our findings provide first evidence on the release of CXCL5 in UV‐radiated human skin and the essential role of fibroblast‐keratinocyte interaction in the regulation of epidermal CXCL5.

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“…Interaction between tumor cells and their microenvironment is a highly dynamic process, with presumed effects on tumor progression. The interplay is based on three basic processes: production of autocrine and paracrine factors, cell-matrix contact, and signaling by direct cell-cell interactions (39,40). To establish cell culture models for the study of the tumorigenesis of human pancreatic cancer in vitro, we have developed immortalized cultures of HPDE cells derived from normal epithelium (41).…”

Section: Discussionmentioning

confidence: 99%