IL-1R-MyD88 signaling in keratinocyte transformation and carcinogenesis

Christophe Cataisson, Rosalba Salcedo, Shakeeb Hakim, A. Moffitt B. Andrea, Lisa Wright, Ming Yi, Robert Stephens, Ren Ming Dai, Lyudmila Lyakh, Dominik Schenten, H. Stuart Yuspa, Giorgio Trinchieri

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Constitutively active RAS plays a central role in the development of human cancer and is sufficient to induce tumors in two-stage skin carcinogenesis. RAS-mediated tumor formation is commonly associated with up-regulation of cytokines and chemokines that mediate an inflammatory response considered relevant to oncogenesis. In this study, we report that mice lacking IL-1R or MyD88 are less sensitive to topical skin carcinogenesis than their respective wild-type (WT) controls. MyD88 -/- or IL-1R -/- keratinocytes expressing oncogenic RAS are hyperproliferative and fail to up-regulate proinflammatory genes or down-regulate differentiation markers characteristic of RAS-expressing WT keratinocytes. Although RAS-expressing MyD88 -/- keratinocytes form only a few small tumors in ortho- topic grafts, IL-1R-deficient RAS-expressing keratinocytes retain the ability to form tumors in orthotopic grafts. Using both genetic and pharmacological approaches, we find that the differentiation and proinflammatory effects of oncogenic RAS in keratinocytes require the establishment of an autocrine loop through IL-1α, IL-1R, and MyD88 leading to phosphorylation of IκBα and NF-κB activation. Blocking IL-1α-mediated NF-κB activation in RAS-expressing WT keratinocytes reverses the differentiation defect and inhibits proinflammatory gene expression. Collectively, these results demonstrate that MyD88 exerts a cell-intrinsic function in RAS-mediated transformation of keratinocytes.

Original languageEnglish (US)
Pages (from-to)1689-1702
Number of pages14
JournalJournal of Experimental Medicine
Volume209
Issue number9
DOIs
StatePublished - Aug 2012
Externally publishedYes

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Keratinocytes
Carcinogenesis
Neoplasms
Interleukin-1
Up-Regulation
Transplants
Skin
Aptitude
Differentiation Antigens
Human Development
Chemokines
Down-Regulation
Phosphorylation
Pharmacology
Cytokines
Gene Expression
Genes

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Cataisson, C., Salcedo, R., Hakim, S., Moffitt B. Andrea, A., Wright, L., Yi, M., ... Trinchieri, G. (2012). IL-1R-MyD88 signaling in keratinocyte transformation and carcinogenesis. Journal of Experimental Medicine, 209(9), 1689-1702. https://doi.org/10.1084/jem.20101355

IL-1R-MyD88 signaling in keratinocyte transformation and carcinogenesis. / Cataisson, Christophe; Salcedo, Rosalba; Hakim, Shakeeb; Moffitt B. Andrea, A.; Wright, Lisa; Yi, Ming; Stephens, Robert; Dai, Ren Ming; Lyakh, Lyudmila; Schenten, Dominik; Yuspa, H. Stuart; Trinchieri, Giorgio.

In: Journal of Experimental Medicine, Vol. 209, No. 9, 08.2012, p. 1689-1702.

Research output: Contribution to journalArticle

Cataisson, C, Salcedo, R, Hakim, S, Moffitt B. Andrea, A, Wright, L, Yi, M, Stephens, R, Dai, RM, Lyakh, L, Schenten, D, Yuspa, HS & Trinchieri, G 2012, 'IL-1R-MyD88 signaling in keratinocyte transformation and carcinogenesis', Journal of Experimental Medicine, vol. 209, no. 9, pp. 1689-1702. https://doi.org/10.1084/jem.20101355
Cataisson C, Salcedo R, Hakim S, Moffitt B. Andrea A, Wright L, Yi M et al. IL-1R-MyD88 signaling in keratinocyte transformation and carcinogenesis. Journal of Experimental Medicine. 2012 Aug;209(9):1689-1702. https://doi.org/10.1084/jem.20101355
Cataisson, Christophe ; Salcedo, Rosalba ; Hakim, Shakeeb ; Moffitt B. Andrea, A. ; Wright, Lisa ; Yi, Ming ; Stephens, Robert ; Dai, Ren Ming ; Lyakh, Lyudmila ; Schenten, Dominik ; Yuspa, H. Stuart ; Trinchieri, Giorgio. / IL-1R-MyD88 signaling in keratinocyte transformation and carcinogenesis. In: Journal of Experimental Medicine. 2012 ; Vol. 209, No. 9. pp. 1689-1702.
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