The mitogen-activated protein kinases p38 and ERK1/2 are increased in lesional psoriatic skin

Johansen, Claus; Kragballe, Knud; Westergaard, Majken; Henningsen, J.; Kristiansen, Karsten; Iversen, Lars

doi:10.1111/j.1365-2133.2004.06304.x

Cited by 183 publications

(205 citation statements)

References 29 publications

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“…43 Of note, increased kinase activities of p38α, p38β and p38δ isoforms are detected in lesional compared with nonlesional psoriatic skin. 49 Altogether, these data support the notion that p38 isoform-specific signaling may play distinct roles in regulation of epidermal homeostasis and may differentially contribute to the pathogenesis of various cutaneous pathologies, possibly via responding to different stimuli, as well as by targeting distinct sets of substrates.…”

Section: The Role Of P38δ In Regulation Of Keratinocyte Functionsupporting

confidence: 68%

p38δ mitogen-activated protein kinase regulates skin homeostasis and tumorigenesis

Efimova¹

2010

Cell Cycle

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Section: The Role Of P38δ In Regulation Of Keratinocyte Functionsupporting

confidence: 68%

p38δ mitogen-activated protein kinase regulates skin homeostasis and tumorigenesis

Efimova¹

2010

Cell Cycle

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“…Intracellular signaling pathways and their role in psoriasis have recently attracted much interest, and signaling pathways such as the NF-κB, JAK/STAT, and p38 MAPK pathway have been demonstrated to be altered in psoriatic skin (11,(28)(29)(30). Here, we identify for the first time to our knowledge IκBζ as a key regulator in the development of psoriasis and as an important transcriptional coactivator mediating downstream effects of IL-17A.…”

Section: Discussionmentioning

confidence: 75%

IκBζ is a key driver in the development of psoriasis

Johansen

Mose

Ommen

et al. 2015

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

105

132

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Psoriasis is a common immune-mediated, chronic, inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells. Although TNFα-and IL-17A-targeting drugs have recently proven to be highly effective, the molecular mechanism underlying the pathogenesis of psoriasis remains poorly understood. We found that expression of the atypical IκB member IκB (inhibitor of NF-κB) ζ, a selective coactivator of particular NF-κB target genes, was strongly increased in skin of patients with psoriasis. Moreover, in human keratinocytes IκBζ was identified as a direct transcriptional activator of TNFα/IL-17A-inducible psoriasis-associated proteins. Using genetically modified mice, we found that imiquimod-induced psoriasis-like skin inflammation was completely absent in IκBζ-deficient mice, whereas skin inflammation was still inducible in IL-17A-and TNFα-deficient mice. IκBζ deficiency also conferred resistance against IL-23-induced psoriasis. In addition, local abrogation of IκBζ function by intradermal injection of IκBζ siRNA abolished psoriasis-like skin inflammation. Taken together, we identify IκBζ as a hitherto unknown key regulator of IL-17A-driven effects in psoriasis. Thus, targeting IκBζ could be a future strategy for treatment of psoriasis, and other inflammatory diseases for which IL-17 antagonists are currently tested in clinical trials.

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“…According to earlier studies, keratinocytes of hyperplastic epidermis express high levels of pERK with the classical nuclear localization, whereas keratinocytes of normal skin show low pERKs levels with a main cytoplasmic localization. [45][46][47] We have topically treated a psoriatic lesion with NaHS at the same concentration found in most balneotherapies. This treatment clearly reduced pERKs expression in the lesion, both at nuclear and cytoplasmic levels.…”

Section: H2s Downregulates Erk In Keratinocytesmentioning

confidence: 99%

Hydrogen sulfide impairs keratinocyte cell growth and adhesion inhibiting mitogen-activated protein kinase signaling

Gobbi

Ricci

Malinverno

et al. 2009

Laboratory Investigation

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The effects of exogenous hydrogen sulfide (H 2 S) on normal skin-derived immortalized human keratinocytes have been investigated in detail. We show in vitro that exogenous hydrogen sulfide reduces clonal growth, cell proliferation and cell adhesion of human keratinocytes. H 2 S, in fact, decreases the frequency of the putative keratinocyte stem cell subpopulation in culture, consequently affecting clonal growth, and impairs cell proliferation and adhesion of mature cells. As a mechanistic explanation of these effects, we show at the molecular level that (i) H 2 S reduces the Raf/MAPK kinase/ERK signaling pathway; (ii) the reduced adhesion of sulfur-treated cells is associated to the downregulation of the expression of b4, a2 and a6 integrins that are necessary to promote cell adhesion as well as anti-apoptotic and proliferative signaling in normal keratinocytes. One specific interest of the effects of sulfurs on keratinocytes derives from the potential applications of the results, as sulfur is able to penetrate the skin and a sulfur-rich balneotherapy has been known for long to be effective in the treatment of psoriasis. Thus, the relevance of our findings to the pathophysiology of psoriasis was tested in vivo by treating psoriatic lesions with sulfurs at a concentration comparable to that most commonly found in sulfurous natural springs. In agreement with the in vitro observations, the immunohistochemical analysis of patient biopsies showed a specific downregulation of ERK activation levels, the key molecular event in the sulfur-induced effects on keratinocytes.

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The mitogen-activated protein kinases p38 and ERK1/2 are increased in lesional psoriatic skin

Cited by 183 publications

References 29 publications

p38δ mitogen-activated protein kinase regulates skin homeostasis and tumorigenesis

p38δ mitogen-activated protein kinase regulates skin homeostasis and tumorigenesis

IκBζ is a key driver in the development of psoriasis

Hydrogen sulfide impairs keratinocyte cell growth and adhesion inhibiting mitogen-activated protein kinase signaling

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