Localized Inflammatory Skin Disease Following Inducible Ablation of I Kappa B Kinase 2 in Murine Epidermis

Stratis, Athanasios; Pasparakis, Manolis; Markur, Doreen; Knaup, Renate; Pofahl, Ruth; Metzger, Daniel; Chambon, Pierre; Krieg, Thomas; Haase, Ingo

doi:10.1038/sj.jid.5700092

Cited by 37 publications

(32 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previously published data (13)(14)(15)23) indicate an important role for IKKb in the development and functionality of skin. The diverse phenotypes observed in other stratified epithelia and exocrine glands of K5-IKKb Tg mice indicate the importance of IKKb also in these organs and tissues.…”

Section: Discussionmentioning

confidence: 99%

IKKβ Overexpression Leads to Pathologic Lesions in Stratified Epithelia and Exocrine Glands and to Tumoral Transformation of Oral Epithelia

Page

Cascallana

Casanova

et al. 2011

Molecular Cancer Research

View full text Add to dashboard Cite

Alterations in nuclear factor kappaB (NFkB) signaling have been related with several diseases and importantly also with cancer. Different animal models with increased or diminished NFkB signaling have shown that NFkB subunits and their regulators are relevant to the pathophysiology of different organs and tissues. In particular, both the deletion of the regulatory subunit b of the kinase of the inhibitor of NFkB (IKKb) and its overexpression in epidermis lead to the development of skin inflammatory diseases not associated with tumoral lesions. In this work, we have studied the consequences of IKKb overexpression in other organs and tissues. We found that elevated IKKb levels led to altered development and functionality of exocrine glands (i.e., mammary glands) in transgenic female mice. In oral epithelia, increased IKKb expression produced lichenoid inflammation with abundant granulocytes, macrophages, and B cells, among other inflammatory cells. This inflammatory phenotype was associated with high incidence of tumoral lesions in oral epithelia, contrary to what was found in skin. Moreover, IKKb also increased the malignant progression of both spontaneous and experimentally induced oral tumors. These results highlight the importance of IKKb in epithelial and glandular homeostasis as well as in oral tumorigenesis and open the possibility that IKKb activity might be implicated in the development of oral cancer in humans. Mol Cancer Res; 9(10); 1329-38. Ó2011 AACR.

show abstract

Section: Discussionmentioning

confidence: 99%

IKKβ Overexpression Leads to Pathologic Lesions in Stratified Epithelia and Exocrine Glands and to Tumoral Transformation of Oral Epithelia

Page

Cascallana

Casanova

et al. 2011

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…The postnatal development of the disease suggests that environmental factors could be implicated in triggering the lesions. Moreover, using inducible models, skin inflammation could also be induced after genetic ablation of NEMO or IKK2 in adult skin [79,88], suggesting that the development of skin lesions is not triggered by developmental processes occurring in the early postnatal skin.…”

Section: Keratinocyte-restricted Inhibition Of Nf-κb Induces Skin Infmentioning

confidence: 99%

NF-κB in the regulation of epithelial homeostasis and inflammation

2010

Self Cite

View full text Add to dashboard Cite

The IκB kinase/NF-κB signaling pathway has been implicated in the pathogenesis of several inflammatory diseases. Increased activation of NF-κB is often detected in both immune and non-immune cells in tissues affected by chronic inflammation, where it is believed to exert detrimental functions by inducing the expression of proinflammatory mediators that orchestrate and sustain the inflammatory response and cause tissue damage. Thus, increased NF-κB activation is considered an important pathogenic factor in many acute and chronic inflammatory disorders, raising hopes that NF-κB inhibitors could be effective for the treatment of inflammatory diseases. However, ample evidence has accumulated that NF-κB inhibition can also be harmful for the organism, and in some cases trigger the development of inflammation and disease. These findings suggested that NF-κB signaling has important functions for the maintenance of physiological immune homeostasis and for the prevention of inflammatory diseases in many tissues. This beneficial function of NF-κB has been predominantly observed in epithelial cells, indicating that NF-κB signaling has a particularly important role for the maintenance of immune homeostasis in epithelial tissues. It seems therefore that NF-κB displays two faces in chronic inflammation: on the one hand increased and sustained NF-κB activation induces inflammation and tissue damage, but on the other hand inhibition of NF-κB signaling can also disturb immune homeostasis, triggering inflammation and disease. Here, we discuss the mechanisms that control these apparently opposing functions of NF-κB signaling, focusing particularly on the role of NF-κB in the regulation of immune homeostasis and inflammation in the intestine and the skin.

show abstract

“…Further processing, paraffin embedding of paraformaldehyde fixed tissue and H-E staining was according to standard histopathological procedures. Immunostaining of keratin 14, keratin 10 and loricrin was performed as described in (Stratis et al, 2006). For staining of E-cadherin, integrins, matrix proteins, Rac and the Myc-tag the following antibodies and procedures were applied on frozen sections: E-cadherin, antibody GP84 (kindly provided by Rolf Kemler, Max-Planck-Institute of Immunobiology, Freiburg, Germany) at 1:400, 4% paraformaldehyde fixed tissue; ␣ 2 integrin, antibody M075-0 (emfret, Würzburg, Germany) at 1:200, acetone fixed tissue; ␤ 1 integrin, MAB1997 (Chemicon, California, CA) at 1:200, acetone fixed tissue; collagen IV, antibody CL50451AP (Cedarlane, Ontario, Canada) at 1:1500, acetone fixed tissue; laminin 5, antibody 8LN5 (kindly provided by Manuel Koch, Institute of Biochemistry, University of Cologne, Germany) at 1:100, acetone fixed tissue; Rac, antibody 23A8 (Sigma) at 1:100, 4% paraformaldehyde fixed tissue; Myc-tag, antibody 9B11 (Cell Signalling Technology, Frankfurt, Germany) at 1:1000, 4% paraformaldehyde fixed tissue.…”

Section: Histopathological Analysis and Immunostainingmentioning

confidence: 99%

Impaired epidermal wound healing in vivo upon inhibition or deletion of Rac1

Tscharntke

Pofahl

Chrostek-Grashoff

et al. 2007

Journal of Cell Science

Self Cite

102

101

View full text Add to dashboard Cite

To address the functions of Rac1 in keratinocytes of the basal epidermal layer and in the outer root sheath of hair follicles, we generated transgenic mice expressing a dominant inhibitory mutant of Rac, N17Rac1, under the control of the keratin 14 promoter. These mice do not exhibit an overt skin phenotype but show protracted skin wound re-epithelialization. Investigation into the underlying mechanisms revealed that in vivo both proliferation of wound-edge keratinocytes and centripetal migration of the neo-epidermis were impaired. Similar results were obtained in mice with an epidermis-specific deletion of Rac1. Primary epidermal keratinocytes that expressed the N17Rac1 transgene were less proliferative than control cells and showed reduced ERK1/2 phosphorylation upon growth factor stimulation. Adhesion, spreading, random migration and closure of scratch wounds in vitro were significantly inhibited on collagen I and, to a lesser extent, on fibronectin. Stroboscopic analysis of cell dynamics (SACED) of N17Rac1 transgenic and control keratinocytes identified decreased lamella-protrusion persistence in connection with increased ruffle frequency as a probable mechanism for the observed impairment of keratinocyte adhesion and migration. We conclude that Rac1 is functionally required for normal epidermal wound healing and, in this context, exerts a dual function – namely the regulation of keratinocyte proliferation and migration.

show abstract

Localized Inflammatory Skin Disease Following Inducible Ablation of I Kappa B Kinase 2 in Murine Epidermis

Cited by 37 publications

References 16 publications

IKKβ Overexpression Leads to Pathologic Lesions in Stratified Epithelia and Exocrine Glands and to Tumoral Transformation of Oral Epithelia

IKKβ Overexpression Leads to Pathologic Lesions in Stratified Epithelia and Exocrine Glands and to Tumoral Transformation of Oral Epithelia

NF-κB in the regulation of epithelial homeostasis and inflammation

Impaired epidermal wound healing in vivo upon inhibition or deletion of Rac1

Contact Info

Product

Resources

About