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J. Biol. Chem., Vol. 280, Issue 8, 7010-7021, February 25, 2005

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Interleukin-8 Induces Nuclear Transcription Factor-B through a TRAF6-dependent Pathway^*

Sunil K. Manna and Govindarajan T. Ramesh¶

From the Laboratory of Immunology, Centre for DNA Fingerprinting & Diagnostics, Nacharam, Hyderabad 500 076, India and the ^¶Department of Biology, Texas Southern University, Houston, Texas 77004

Considering the potential role of interleukin-8 (IL-8) in inflammation, angiogenesis, tumorigenesis, and metastasis, we investigated the molecular mechanism involved in IL-8-mediated signaling. In this report we provide evidence that like TNF, an inducer of NF-B and also a NF-B-dependent gene product, IL-8 induces NF-B in a unique pathway. IL-8 induces NF-B activation in a dose-dependent manner in different cell types as detected by a DNA-protein binding assay. IL-8 induces NF-B-dependent reporter gene expression as well as ICAM-1, VCAM-1, and Cox-2 expression. IL-8 also induces IB phosphorylation followed by degradation and p65 translocation. IL-8 induces c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase (MAPK) in a dose- and time-dependent manner. IL-8-induced NF-B activation is for the most part unaltered when cells are transfected with dominant-negative TRADD, FADD, or TRAF2, but is inhibited with dominant-negative TRAF6-, NIK-, IKK-, or IB-transfected cells. The data suggest that IL-8-induced NF-B activation proceeds through a TRAF2-independent but TRAF6-dependent pathway, followed by recruitment of IRAK and activation of IKK. IL-8-induced NF-B activation is not observed in a cell-permeable peptide that has TRAF6 binding motif-treated cells or IRAK-deficient cells. IL-8-induced NF-B activation proceeds mostly through interaction with TRAF6 and partially through the Rho-GTPase pathways. This is the first report that IL-8 induces NF-B in a distinct pathway, and activation of NF-B and its dependent genes may be one of the pathways of IL-8-induced inflammation and angiogenesis.

Received for publication, September 24, 2004 , and in revised form, December 7, 2004.

^* This work was supported by the core grant of Centre for DNA Fingerprinting and Diagnostics (CDFD) and Department of Biotechnology (DBT), Government of India, and National Institutes of Health/RCMI Grant RR03045-16. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 011-91-40-27171478; Fax: 011-91-40-27155610; E-mail: manna{at}cdfd.org.in.

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