Interleukin‐13 stimulates interleukin‐6 production by human keratinocytes

Derocq, Jean-Marie; Ségui, M; Poinot-Chaze, C.; Minty, Adrian; Caput, Daniel; Ferrara, Pascual; Casellas, Pierre

doi:10.1016/0014-5793(94)80601-2

Cited by 57 publications

(29 citation statements)

References 27 publications

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“…IL-4 down-regulates IL-6 production in human and murine monocytes, in contrast to what is described for keratinocytes (3,12). Thus, IL-4 regulates the IL-6 gene in opposite ways depending on the origin of its target cells (hematopoietic or not).…”

Section: Il-4contrasting

confidence: 39%

Interleukin-4 Induces Activation of Mitogen-activated Protein Kinase and Phosphorylation of Shc in Human Keratinocytes

Wery

Letourneur

Bertoglio

et al. 1996

Journal of Biological Chemistry

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Most cytokines stimulate the p21ras pathway, leading to MAP kinase activation. One exception is interleukin-4 (IL-4), which has been shown not to activate this pathway in hematopoietic cells. However, IL-4 acts on a broad range of cells, including keratinocytes, in which it induces IL-6 production. We report here that IL-4 stimulation of human keratinocytic cell lines or primary cultures activates MAP kinase. In these cells, IL-4 stimulation induces the tyrosine phosphorylation of p42/44 MAP kinase as well as its catalytic activity. We also observed an increased phosphorylation of p46 shc , an SH2-containing protein involved in the Ras pathway, as a result of IL-4 stimulation in human keratinocytic cell lines but not in T lymphocytes. IL-41 is a cytokine produced by cells of hematopoietic origin, which acts on a broad range of cells of both hematopoietic and non-hematopoietic origin (1, 2). Among the latter, epidermal keratinocytes, which represent the major cell type of the skin, are able to produce IL-6 in response to IL-4 stimulation (3). Even though the IL-4 receptor (IL-4R) lacks a tyrosine kinase domain, IL-4 stimulation results in an increased tyrosine phosphorylation of a variety of intracellular substrates, including a 170-kDa protein, designated as 4PS in hematopoietic cells (4 -6). 4PS is both structurally and functionally similar to IRS-1, the most prominent substrate phosphorylated in response to insulin or insulin-like growth factor-1 stimulation in cells of connective tissue origin (7,8). The amino acid sequence of 4PS (now called IRS-2) has recently been reported, and its alignment with that of IRS-1 revealed highly conserved stretches, which encompass the domains of interaction with SH2-containing proteins p85 and Grb2 (8). IL-4 induces the phosphorylation of 4PS/IRS-1 but fails to activate the p21 ras pathway in hematopoietic cells. Indeed, neither phosphorylation of Shc nor the conversion of Ras to its active GTP-bound conformation has been observed, correlating with a lack of Raf-1 or MAP kinase activation (9, 10). However, IL-4 does activate the phosphatidylinositol 3-kinase whose p85 subunit is known to bind to 4PS in an IL-4-inducible manner (4, 11).IL-4 down-regulates IL-6 production in human and murine monocytes, in contrast to what is described for keratinocytes (3, 12). Thus, IL-4 regulates the IL-6 gene in opposite ways depending on the origin of its target cells (hematopoietic or not). We therefore investigated the possibility that alternate signal transduction pathways, which could account for these differences, may be triggered in various cell types. We indeed observed an increased tyrosine phosphorylation of MAP kinase, which is accompanied by an enhanced catalytic activity of the enzyme following IL-4 stimulation. We also report here that in keratinocytes, but not in T cell blasts, Shc is in fact phosphorylated, suggesting its possible implication in MAP kinase activation in keratinocytes in response to IL-4. EXPERIMENTAL PROCEDURES Materials and AntibodiesRecombinant human IL-4 ...

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Section: Il-4contrasting

confidence: 39%

Interleukin-4 Induces Activation of Mitogen-activated Protein Kinase and Phosphorylation of Shc in Human Keratinocytes

Wery

Letourneur

Bertoglio

et al. 1996

Journal of Biological Chemistry

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“…Treatment of keratinocytes by IL-4 induced production of IL-6 (Derocq et al, 1994). We therefore investigated whether p38 MAPK could be implicated in this regulation.…”

Section: Il-4 Activates the P38 Mapk Signal Transduction Pathwaymentioning

confidence: 99%

“…In these diseases, T-cell in®ltrates are frequently observed and thought to play an important role in sustaining a chronic in¯ammatory process. IL-4, a product of T-helper cells, has been shown to up-regulate IL-6 production in endothelial cells (Howells et al, 1991), in ®broblasts (Doucet et al, 1998;Feghali et al, 1992) and in keratinocytes (Derocq et al, 1994;Kupper et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

IL-4 regulation of IL-6 production involves Rac/Cdc42- and p38 MAPK-dependent pathways in keratinocytes

et al. 2000

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“…IL-4 and IL-13 also have pro-in¯ammatory e ects on other cell types. In particular, IL-4 and IL-13 enhance IL-6 expression by endothelial cells and keratinocytes (Colotta et al, 1992;Derocq et al, 1994). These overlapping activities of IL-4 and IL-13 are conferred by the existence of common receptor components.…”

Section: Introductionmentioning

confidence: 99%

Induction of the IL-13 receptor α2-chain by IL-4 and IL-13 in human keratinocytes: involvement of STAT6, ERK and p38 MAPK pathways

et al. 2001

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IL-4 and IL-13 are related cytokines which induce both pro-and anti-in¯ammatory e ects depending on the cell type they act upon and the nature of the receptors expressed. The type I receptor complex is composed of the IL-4Ra and gc and only binds IL-4, whereas, in the type II receptor, IL-4Ra dimerizes with IL-13Ra1 upon either IL-4 or IL-13 binding. Another ligand binding chain potentially implicated in the IL-4/IL-13 receptor has been described, the IL-13Ra2, but the regulation of its expression and its role in IL-4/IL-13 transduction is poorly understood. In this study we report that IL-4 and IL-13 upregulate IL-13Ra2 at both the mRNA and protein levels in the keratinocyte cell line HaCaT. In these cells, IL-4 or IL-13 were shown to activate the Janus Kinases JAK1 and JAK2, the transcription factor STAT6, and the ERK and p38 mitogen-activated protein kinases. We show that IL-4 or IL-13-induced IL-13Ra2 mRNA expression was inhibited by the ERK inhibitor U0126, the JAK inhibitor AG490 and, to a lesser extent, the p38 MAPK inhibitor SB203580. Moreover, expression of a constitutive active mutant of STAT6 alone did not modify IL-13Ra2 mRNA expression, but potentiated the e ects of IL-4 or IL-13 on IL-13Ra2 expression. The constitutive active mutants of MEK1 or MKK6 increased the level of expression of IL-13Ra2 mRNA even in absence of stimulation. Our ®ndings demonstrate, for the ®rst time, that IL-4 and IL-13 can induce IL-13Ra2 expression in keratinocytes, and that the ERK and p38 MAPK together with JAK2 and STAT6 play a critical role in this process. Oncogene (2001) 20, 6660 ± 6668.

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Interleukin‐13 stimulates interleukin‐6 production by human keratinocytes

Cited by 57 publications

References 27 publications

Interleukin-4 Induces Activation of Mitogen-activated Protein Kinase and Phosphorylation of Shc in Human Keratinocytes

Interleukin-4 Induces Activation of Mitogen-activated Protein Kinase and Phosphorylation of Shc in Human Keratinocytes

IL-4 regulation of IL-6 production involves Rac/Cdc42- and p38 MAPK-dependent pathways in keratinocytes

Induction of the IL-13 receptor α2-chain by IL-4 and IL-13 in human keratinocytes: involvement of STAT6, ERK and p38 MAPK pathways

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