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A Distinct Role of Neutrophil Lactoferrin in RelA/p65 Phosphorylation on Ser⁵³⁶ by Recruiting TNF Receptor-Associated Factors to IB Kinase Signaling Complex¹

Sang-Muk Oh^2,*, Shin-Hee Lee^*, Bum-Jin Lee^*, Chul-Woong Pyo^*, Na-Kyung Yoo^*, Soo Young Lee, Jiyoung Kim and Sang-Yun Choi^3,*

^* School of Life Sciences and Biotechnology, Korea University, Seoul, Korea; Division of Molecular Life Sciences, Ewha Womans University, Seoul, Korea; and Graduate School of Biotechnology, Kyung Hee University, Yongin, Korea

The activation of NF-B by neutrophil lactoferrin (Lf) is regulated via the IB kinase (IKK) signaling cascade, resulting in the sequential phosphorylation and degradation of IB. In this study, we observed that Lf protein augmented p65 phosphorylation at the Ser⁵³⁶, but not the Ser²⁷⁶ residue, and stimulated the translocation of p65 into the nucleus. Lf was also shown to enhance the association between p65 and CREB-binding protein/p300 in vivo. To elucidate the mechanism by which Lf triggers these signaling pathways, we attempted to delineate the roles of the upstream components of the IKK complex, using their dominant-negative mutants and IKK^–/– and IKK^–/– mouse embryonic cells. We demonstrated that both IKK and IKK as well as NF-B-inducing kinase are indispensable for Lf-induced p65 phosphorylation. However, MAPK kinase kinase 1 is not essentially required for this activation. We also observed that Lf-induced p65 phosphorylation was either partially or completely abrogated as the result of treatment with the mutant forms of TNFR-associated factor (TRAF) 2, TRAF5, or TRAF6. Moreover, we demonstrated that Lf directly interacted with TRAF5. Expression of the dominant-negative mutant of TRAF5 or its small interfering RNA almost completely abrogated the Lf-induced p65 phosphorylation. These results suggest that signaling pathways, including TRAFs/NF-B-inducing kinase/IKKs, may be involved in the regulation of Lf-induced p65 activation, thereby resulting in the activation of members of the NF-B family.

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.

¹ This work was supported by Grant R01-2004-000-10481-0 from the Basic Research Program of the Korea Science & Engineering Foundation.

² Current address: Emory University School of Medicine, Atlanta, GA 30322.

³ Address correspondence and reprint requests to Dr. Sang-Yun Choi, School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea. E-mail address: sychoi{at}korea.ac.kr

⁴ Abbreviations used in this paper: IKK, IB kinase; CAT, chloramphenicol acetyltransferase; HDAC, histone deacetylases; Lf, lactoferrin; MAP3K, MAPK kinase kinase; MEF, mouse embryo fibroblast; MEKK, MAPK kinase kinase; siRNA, small interfering RNA; TRAF, TNF receptor-associated factor; TSA, trichostatin A; CBP, CREB-binding protein.

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