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Differential modulation of keratin expression by sulforaphane occurs via Nrf2-dependent and -independent pathways in skin epithelia.

ABSTRACT: Treatment with the natural chemical sulforaphane (SF) ameliorates skin blistering in keratin 14 (K14)-deficient mice, correlating with the induction of K16 and K17 in the basal layer of epidermis (Kerns et al., PNAS 104:14460, 2007). Here we address the basis for the SF-mediated K16 and K17 induction in mouse epidermis in vivo. As expected, induction of K16 partly depends on the transcription factor Nrf2, which is activated by SF exposure. Strikingly, K17 induction occurs independently of Nrf2 activity and parallels the decrease in glutathione occurring shortly after epidermal exposure to SF. Pharmacological manipulation of glutathione levels in mouse epidermis in vivo alters K17 and K16 expression in the expected manner. We present findings suggesting that select MAP kinases participate in mediating the Nrf2- and glutathione-dependent alterations in K16 and K17 levels in SF-treated epidermis. These findings advance our understanding of the effect of SF on gene expression in epidermis, point to a role for glutathione in mediating some of these effects, and establish that SF induces the expression of two contiguous and highly related genes, K16 and K17, via distinct mechanisms.

SUBMITTER: Kerns M

PROVIDER: S-EPMC2993737 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Differential modulation of keratin expression by sulforaphane occurs via Nrf2-dependent and -independent pathways in skin epithelia.

Kerns Michelle M DePianto Daryle D Yamamoto Masayuki M Coulombe Pierre A PA

Molecular biology of the cell 20101006 23

Treatment with the natural chemical sulforaphane (SF) ameliorates skin blistering in keratin 14 (K14)-deficient mice, correlating with the induction of K16 and K17 in the basal layer of epidermis (Kerns et al., PNAS 104:14460, 2007). Here we address the basis for the SF-mediated K16 and K17 induction in mouse epidermis in vivo. As expected, induction of K16 partly depends on the transcription factor Nrf2, which is activated by SF exposure. Strikingly, K17 induction occurs independently of Nrf2 a ...[more]

PMID: 20926689

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Project description:The transcription factor Nrf2 coordinates a multifaceted response to various forms of stress and to inflammatory processes, maintaining a homeostatic intracellular environment. Nrf2 anti-inflammatory activity has been related to the crosstalk with the transcription factor NF-κB, a pivotal mediator of inflammatory responses and of multiple aspects of innate and adaptative immune functions. However, the underlying molecular basis has not been completely clarified. By combining into new chemical entities, the hydroxycinnamoyl motif from curcumin and the allyl mercaptan moiety of garlic organosulfur compounds, we tested a set of molecules, carrying (pro)electrophilic features responsible for the activation of the Nrf2 pathway, as valuable pharmacologic tools to dissect the mechanistic connection between Nrf2 and NF-κB. We investigated whether the activation of the Nrf2 pathway by (pro)electrophilic compounds may interfere with the secretion of pro-inflammatory cytokines, during immune stimulation, in a human immortalized monocyte-like cell line (THP-1). The capability of compounds to affect the NF-κB pathway was also evaluated. We assessed the compounds-mediated regulation of cytokine and chemokine release by using Luminex X-MAP® technology in human primary peripheral blood mononuclear cells (PBMCs) upon LPS stimulation. We found that all compounds, also in the absence of electrophilic moieties, significantly suppressed the LPS-evoked secretion of pro-inflammatory cytokines such as TNFα and IL-1β, but not of IL-8, in THP-1 cells. A reduction in the release of pro-inflammatory mediators similar to that induced by the compounds was also observed after siRNA mediated-Nrf2 knockdown, thus indicating that the attenuation of cytokine secretion cannot be directly ascribed to the activation of Nrf2 signaling pathway. Moreover, all compounds, with the exception of compound 1, attenuated the LPS-induced activation of the NF-κB pathway, by reducing the upstream phosphorylation of IκB, the NF-κB nuclear translocation, as well as the activation of NF-κB promoter. In human PBMCs, compound 4 and CURC attenuated TNFα release as observed in THP-1 cells, and all compounds acting as Nrf2 inducers significantly decreased the levels of MCP-1/CCL2, as well as the release of the pro-inflammatory cytokine IL-12. Altogether, the compounds induced a differential modulation of innate immune cytokine release, by differently regulating Nrf2 and NF-κB intracellular signaling pathways.

Dataset Information

Differential modulation of keratin expression by sulforaphane occurs via Nrf2-dependent and -independent pathways in skin epithelia.

Publications

Differential modulation of keratin expression by sulforaphane occurs via Nrf2-dependent and -independent pathways in skin epithelia.

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