Regulation of Interleukin-1α Expression by Integrins and Epidermal Growth Factor Receptor in Keratinocytes from a Mouse Model of Inflammatory Skin Disease

Hobbs, Robin M.; Watt, Fiona M.

doi:10.1074/jbc.m300513200

Cited by 42 publications

(43 citation statements)

References 88 publications

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“…Our results show that the MEK/ERK signaling pathway was essential for IL-1␣ transcription. Similar findings have been demonstrated in previous studies (42,43). Additional experiments are required for understanding of the functional role of the MEK/ERK pathway in PGE 2 induction of IL-1␣ transcription, because PGE 2 has been shown to transactivate the MEK/ERK signaling pathway via different mechanisms (15,20,36).…”

Section: Discussionsupporting

confidence: 84%

Prostaglandin E2 Induces the Expression of IL-1α in Colon Cancer Cells

Shao

Sheng

2007

The Journal of Immunology

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PGE2 has been shown to exert pro-oncogenic effects in colorectal neoplasia through producing autocrine or paracrine growth factors. In the present study, we demonstrate that PGE2 induced the expression of IL-1α in colon cancer cells, which plays critical roles in tumor metastasis and neoangiogenesis in a variety of cancers. PGE2 increased the levels of both IL-1α mRNA and protein, suggesting a positive feedback loop between the IL-1 pathway and PGE2 signaling. Mechanistically, PGE2 induced the expression of IL-1α at both transcriptional and posttranscriptional levels. PGE2 stimulated the transcriptional activity of the IL-1α promoter and significantly stabilized IL-1α mRNA. Moreover, we show that IL-1α enhanced colorectal neoplasia, stimulating cell migration and neoangiogenesis. Knockdown of the expression of IL-1α by small-interfering RNA resulted in a reduction of vascular endothelial growth factor secretion in colon cancer cells and an inhibition of tube formation by HUVECs. Thus, our results suggest that PGE2 induces the expression of proinflammatory cytokine IL-1α, which may potentially enhance the proneoplastic actions of the cyclooxygenase-2/PGE2 signaling pathway.

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Section: Discussionsupporting

confidence: 84%

Prostaglandin E2 Induces the Expression of IL-1α in Colon Cancer Cells

Shao

Sheng

2007

The Journal of Immunology

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“…As deregulated integrin signaling is associated with constitutive ERK-MAPK activation and this contributes to aberrant growth and differentiation (19,21,22), it is possible that LMP1 induces a hyperkeratotic state and perturbs keratinocyte differentiation by disrupting normal integrin signaling. Indeed, deregulated or constitutive ERK-MAPK signaling plays an important role in the pathogenesis of many epithelial disorders and is implicated in the etiology of both benign and malignant epithelial diseases.…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus-Encoded LMP1 Regulates Epithelial Cell Motility and Invasion via the ERK-MAPK Pathway

Dawson

Laverick

Morris

et al. 2008

J Virol

103

101

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Most of what is known about the biology of Epstein-Barr virus (EBV) relates to its interaction with cells of the B lymphoid lineage. EBV was originally identified on the basis of its association with Burkitt's lymphoma, and the B lymphotropic nature of the virus is confirmed by its ability to readily infect and transform normal resting B cells in vitro (47). The virus, however, can also infect epithelial cells, and this interaction can result in malignant transformation, as exemplified by the consistent association of EBV with nasopharyngeal carcinoma (NPC) and with a proportion of gastric adenocarcinomas (44,47,53). The EBV-induced transformation of B cells in vitro is associated with the expression of two nonpolyadenylated RNAs (EBER1 and EBER2), along with a set of latent viral gene products consisting of six EBV nuclear antigens (EBNA1, EBNA2, EBNA3A, EBNA3B, EBNA3C, and EBNA leader protein) and three latent membrane proteins (LMP1, LMP2A, and LMP2B) (67). However, more restricted patterns of latent gene expression are observed in NPC and in EBV-positive gastric adenocarcinomas, where only the EBERs, EBNA1, and LMP2A are consistently expressed and the expression of LMP1 is either variable or absent (44, 67). While the association of EBV with various lymphoid and epithelial malignancies is well documented, the precise contribution of virus infection to the etiology of these tumors remains unknown.LMP1 is the major transforming protein of EBV, being absolutely essential for B-cell transformation (28) and behaving as a classical oncogenic protein in rodent fibroblast transformation assays (61). LMP1 induces the expression of lymphocyte activation antigens (62, 63) and antiapoptotic proteins (Bcl-2, TNFAIP3, and MCL1) (20,32,64) and stimulates the secretion of cytokines such as interleukin-10 (IL-10), among others (58). When expressed in epithelial cells, LMP1 induces the expression of 12). It can transform certain established epithelial cell lines and block the terminal differentiation of the cells (7,8,15,23), and it induces hyperkeratosis when expressed in transgenic mouse epidermis (65). LMP1 also induces the expression of the epidermal growth factor (EGF) receptor (41, 42, 43) and matrix metalloproteinases (35,54,59) and can down-regulate the expression of E-cadherin (16), findings which suggest that LMP1 can modulate signaling pathways that regulate the motile and invasive properties of epithelial cells. This characteristic is of particular relevance given that LMP1-positive NPC tumors are reportedly more aggressive than their LMP1-negative counterparts (24).LMP1 functions as a constitutively activated member of the tumor necrosis factor receptor superfamily, activating a number of signaling pathways in a ligand-independent manner (18, 30). LMP1 activates both the canonical and noncanonical NF-B pathways (37, 49), can induce AP-1 and p38/ATF2 activity (11,12,13,29,50,60), and has been shown previously to activate phosphatidylinositol 3-kinase (PI 3-kinase)/Akt kinase (2, 9, 39).Although the activation of t...

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“…When activated MEK1 is expressed suprabasally in transgenic mice, there is constitutive epidermal hyperproliferation and inflammation (Hobbs et al 2004). One of the cytokines that is up-regulated on suprabasal epidermal integrin expression is IL1-a (Hobbs and Watt 2003;Hobbs et al 2004). The effect of suprabasal integrin expression on cytokine production is another example of non-cell-autonomous integrin signaling.…”

Section: Epidermal Hyperproliferation and Wound Healingmentioning

confidence: 99%

Cell-Extracellular Matrix Interactions in Normal and Diseased Skin

Watt

Fujiwara²

2011

Cold Spring Harbor Perspectives in Biology

309

269

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Mammalian skin comprises a multi-layered epithelium, the epidermis, and an underlying connective tissue, the dermis. The epidermal extracellular matrix is a basement membrane, whereas the dermal ECM comprises fibrillar collagens and associated proteins. There is considerable heterogeneity in ECM composition within both epidermis and dermis. The functional significance of this extends beyond cell adhesion to a range of cell autonomous and nonautonomous processes, including control of epidermal stem cell fate. In skin, cell-ECM interactions influence normal homeostasis, aging, wound healing, and disease. Disturbed integrin and ECM signaling contributes to both tumor formation and fibrosis. Strategies for manipulating cell-ECM interactions to repair skin defects and intervene in a variety of skin diseases hold promise for the future.

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Regulation of Interleukin-1α Expression by Integrins and Epidermal Growth Factor Receptor in Keratinocytes from a Mouse Model of Inflammatory Skin Disease

Cited by 42 publications

References 88 publications

Prostaglandin E2 Induces the Expression of IL-1α in Colon Cancer Cells

Prostaglandin E2 Induces the Expression of IL-1α in Colon Cancer Cells

Epstein-Barr Virus-Encoded LMP1 Regulates Epithelial Cell Motility and Invasion via the ERK-MAPK Pathway

Cell-Extracellular Matrix Interactions in Normal and Diseased Skin

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