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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.
J Biol Chem. 2002 Jan 11; 277(2):1268-75.JB

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+Show Affiliations

Department of Dermatology, Ulm University, Oberer Eselsberg 40, 89081 Ulm, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11694538

Citation

Huber, Margit A., et al. "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." The Journal of Biological Chemistry, vol. 277, no. 2, 2002, pp. 1268-75.
Huber MA, Denk A, Peter RU, et al. 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. J Biol Chem. 2002;277(2):1268-75.
Huber, M. A., Denk, A., Peter, R. U., Weber, L., Kraut, N., & Wirth, T. (2002). 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. The Journal of Biological Chemistry, 277(2), 1268-75.
Huber MA, et al. 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. J Biol Chem. 2002 Jan 11;277(2):1268-75. PubMed PMID: 11694538.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Huber,Margit A, AU - Denk,Andrea, AU - Peter,Ralf U, AU - Weber,Lutz, AU - Kraut,Norbert, AU - Wirth,Thomas, Y1 - 2001/11/02/ PY - 2001/11/6/pubmed PY - 2002/2/8/medline PY - 2001/11/6/entrez SP - 1268 EP - 75 JF - The Journal of biological chemistry JO - J Biol Chem VL - 277 IS - 2 N2 - 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. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/11694538/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)87923-X DB - PRIME DP - Unbound Medicine ER -