The IKK-2/Ikappa Balpha /NF-kappa B pathway plays a key role in the regulation of CCR3 and eotaxin-1 in fibroblasts. A critical link to dermatitis in Ikappa Balpha -deficient mice.

Abstract	Tumor necrosis factor (TNF)-alpha-induced phosphorylation of the IkappaB proteins by the IkappaB kinase (IKK) complex containing IKK-2 and subsequent degradation of the IkappaB proteins are prerequisites for NF-kappaB activation, resulting in the stimulation of a variety of pro-inflammatory target genes. The C-C chemokine eotaxin-1 is a potent chemoattractant for eosinophils and Th2 lymphocytes, may play an important role in the pathogenesis of atopic dermatitis, and acts via binding to its receptor CCR3. To investigate the role of NF-kappaB signaling in the regulation of these genes, we stably expressed a transdominant mutant of IkappaBalpha and a constitutively active mutant of IKK-2 in mouse NIH3T3 fibroblasts. The transdominant IkappaBalpha mutant completely inhibited TNF-alpha-mediated induction of both eotaxin-1 and CCR3, whereas expression of constitutively active IKK-2 was sufficient to drive almost full expression of these two genes in the absence of TNF-alpha. Moreover, we observed elevated expression levels of CCR3 and eotaxin-1 protein levels in the skin of IkappaBalpha-deficient mice characterized by a widespread dermatitis. Finally, using dermal fibroblasts derived from IkappaBalpha-deficient mice, we observed elevated basal expression, enhanced inducibility by TNF-alpha, and attenuated down-regulation upon TNF-alpha withdrawal of both CCR3 and eotaxin-1 mRNA levels. These results demonstrate that the IKK-2/IkappaBalpha/NF-kappaB pathway plays a critical role for CCR3 and eotaxin-1 expression in fibroblasts and suggests a critical link to the pathogenesis of atopic dermatitis.
Authors	Margit A Huber, Andrea Denk, Ralf U Peter, Lutz Weber, Norbert Kraut, Thomas Wirth
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 277 Issue 2 Pg. 1268-75 (Jan 11 2002) ISSN: 0021-9258 [Print] United States
PMID	11694538 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Ccl11 protein, mouse Ccr3 protein, mouse Chemokine CCL11 Chemokines, CC Chemotactic Factors, Eosinophil DNA-Binding Proteins I-kappa B Proteins NF-kappa B Nfkbia protein, mouse Receptors, CCR3 Receptors, Chemokine Tumor Necrosis Factor-alpha NF-KappaB Inhibitor alpha Protein Serine-Threonine Kinases Chuk protein, mouse I-kappa B Kinase Ikbkb protein, mouse Ikbke protein, mouse
Topics	3T3 Cells Animals Cells, Cultured Chemokine CCL11 Chemokines, CC (metabolism) Chemotactic Factors, Eosinophil (metabolism) DNA-Binding Proteins (genetics, metabolism) Dermatitis, Atopic (metabolism, pathology) Epidermal Cells Epidermis (pathology) Fibroblasts (cytology, drug effects, metabolism) Gene Expression Regulation (physiology) Genes, Reporter I-kappa B Kinase I-kappa B Proteins Immunohistochemistry Mice Mice, Knockout NF-KappaB Inhibitor alpha NF-kappa B (genetics, metabolism) Protein Serine-Threonine Kinases (genetics, metabolism) Receptors, CCR3 Receptors, Chemokine (metabolism) Retroviridae (genetics, metabolism) Signal Transduction Tumor Necrosis Factor-alpha (pharmacology)

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