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A distinct role of neutrophil lactoferrin in RelA/p65 phosphorylation on Ser(536) by recruiting TNF receptor-associated factors to I kappa B kinase signaling complex
- A distinct role of neutrophil lactoferrin in RelA/p65 phosphorylation on Ser(536) by recruiting TNF receptor-associated factors to I kappa B kinase signaling complex
- Oh, Sang-Muk; Lee, Shin-Hee; Lee, Bum-Jin; Pyo, Chul-Woong; Yoo, Na-Kyung; Lee, Soo Young; Kim, Jiyoung; Choi, Sang-Yun
- Ewha Authors
- SCOPUS Author ID
- Issue Date
- Journal Title
- JOURNAL OF IMMUNOLOGY
- vol. 179, no. 9, pp. 5686 - 5692
- AMER ASSOC IMMUNOLOGISTS
- SCI; SCIE; SCOPUS
- The activation of NF-kappa B by neutrophil lactoferrin (Lf) is regulated via the I kappa B kinase (IKK) signaling cascade, resulting in the sequential phosphorylation and degradation of I kappa B. In this study, we observed that Lf protein augmented p65 phosphorylation at the Ser(536), but not the Ser(276) 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 alpha(-/-) and IKK beta(-/-) mouse embryonic cells. We demonstrated that both IKK alpha(-/-) and IKK beta(-/-) as well as NF-kappa 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-kappa 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-kappa B family.
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