Human Neutrophil Lactoferrin trans-Activates the Matrix Metalloproteinase 1 Gene through Stress-activated MAPK Signaling Modules

Oh, Sang Muk; Hahm, Dae Hyun; Kim, Ik Hwan; Choi, Sang-Yun

doi:10.1074/jbc.m107724200

Cited by 57 publications

(40 citation statements)

References 28 publications

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“…Human neutrophil Lf expression vector pLf was as described (23). Plasmids pRK-Flag-IKK␣, pRK-Flag-IKK␤, pRK-Flag-IKK␣ (K44A), pRKFlag-IKK␤ (K44A), and pRK-Flag-NIK (KK429 -430AA) were described previously (21).…”

Section: Plasmids and Small Interfering Rnas (Sirnas)mentioning

confidence: 99%

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

Lee

et al. 2007

The Journal of Immunology

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The activation of NF-κB by neutrophil lactoferrin (Lf) is regulated via the IκB kinase (IKK) signaling cascade, resulting in the sequential phosphorylation and degradation of IκB. 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 IKKα−/− and IKKβ−/− mouse embryonic cells. We demonstrated that both IKKα and IKKβ as well as NF-κB-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-κB-inducing kinase/IKKs, may be involved in the regulation of Lf-induced p65 activation, thereby resulting in the activation of members of the NF-κB family.

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Section: Plasmids and Small Interfering Rnas (Sirnas)mentioning

confidence: 99%

“…After extensive washing, the complexes were subjected to immunoblotting with anti-CBP Ab. For immunoblot analysis using phospho-RelA Abs, 30 g each of nuclear extracts or cell lysates was used and analyzed, as described (23).…”

Section: Immunoblot Analysis and Immunoprecipitationmentioning

confidence: 99%

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

Lee

et al. 2007

The Journal of Immunology

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“…It is thought to play an important role as an innate-defense protein, because its activities include antimicrobial effects (3) and immunomodulatory effects (1), as shown previously by in vitro studies. The in vitro effects of LF are reported to involve activation of the transcription of genes such as matrix metalloproteinase 1, interleukin-1␤ (IL-1␤), tracheal antimicrobial peptide, and p53 tumor suppressor (14,15,22,32).…”

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confidence: 99%

Modulation of Immunity-Related Gene Expression in Small Intestines of Mice by Oral Administration of Lactoferrin

Wakabayashi

Takakura

Yamauchi

et al. 2006

Clin Vaccine Immunol

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Oral administration of lactoferrin (LF), an antimicrobial and immunomodulatory protein, shows a protective effect against infectious diseases, possibly via immunomodulation of the host. Initially, we confirmed an immunomodulatory effect of LF by observing changes in the number of cells in the leukocyte subsets in the peripheral blood and spleens of mice 1 day after oral administration of LF. Then we developed a quantitative reverse transcription-PCR method for 20 immunity-related genes of antimicrobial proteins, pattern recognition receptors, cytokines, and lymphocyte mobilization-related proteins, and we assessed the expression of these genes in the small intestines of mice 2 h after administration of water, bovine serum albumin (BSA), or LF. Expression of the LF gene was lower in mice administered LF than in mice administered water or BSA, implying a negative-feedback control. Expression of gamma interferon (IFN-␥) and interleukin-10 (IL-10) was lower in both BSA-and LF-administered mice than in water administered mice, suggesting a nonspecific effect of protein ingestion. Expression of NOD2, IFN-␤, and IL-12p40 was higher with LF administration than with water or BSA administration. The expression levels of these three genes were correlated. This study indicated that oral administration of LF modulates the small intestinal expression of genes closely related to the host defense in a specific or a nonspecific manner.

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“…13,44 -47 Thus, addition of exogeneous Lf to cell culture media activates the MAPK pathway and leads to cell cycle arrest in MDAMB-231 cells, CD4 upregulation in Jurkat cells and transactivation of the matrix metalloproteinase 1 (MMP1) gene in neutrophils. 23,48,49 Nevertheless, Lf was also observed in the nucleus and it was recently reported that it could enter the nucleus after endocytosis mediated via a specific interaction with a soluble receptor identified as the surface nucleoline. 12,13 Further studies will be necessary to confirm that Lf isoforms induce transcription of genes involved in the control of cell growth and find out whether both forms target the same genes.…”

Section: Discussionmentioning

confidence: 99%

Expression and prognostic value of lactoferrin mRNA isoforms in human breast cancer

Benaı̈ssa

Peyrat

Hornez

et al. 2004

Intl Journal of Cancer

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We investigated the expression levels of human lactoferrin (Lf), a steroid hormone-inducible gene product the expression of which is often altered during oncogenesis, and of ⌬-lactoferrin (⌬Lf), its alternative isoform, which has been shown to be absent from tumor cell lines in commonly used human breast epithelial cell lines, using semiquantitative RT-PCR. Both mRNAs were detected but with levels of expression lower than those found in normal breast epithelial cells. This downregulation was much more visible for ⌬Lf since its expression was either significantly diminished (BT-20, MCF-7 cell lines) or practically absent (MDA-MB-231, T-47D, HBL 100 cell lines). In order to determine whether Lf gene products are useful prognosic tools, we further analyzed their expression levels in 99 primary breast cancer biopsies. ⌬Lf transcripts were found in all of the samples, whereas Lf transcripts were found in 88% of them. Lf and ⌬Lf expression levels were positively correlated (p ‫؍‬ 0.003). Lf expression was related to tumor type with a higher recovery in lobular-type tumors (p ‫؍‬ 0.04). ⌬Lf expression was related to the histoprognostic grading (p ‫؍‬ 0.02). In univariate analyses, ⌬Lf and Lf expressions were prognosis parameters, high concentrations being associated with a longer overall survival.

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Human Neutrophil Lactoferrin trans-Activates the Matrix Metalloproteinase 1 Gene through Stress-activated MAPK Signaling Modules

Cited by 57 publications

References 28 publications

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

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

Modulation of Immunity-Related Gene Expression in Small Intestines of Mice by Oral Administration of Lactoferrin

Expression and prognostic value of lactoferrin mRNA isoforms in human breast cancer

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