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Apoptotic human cells inhibit migration of granulocytes via release of lactoferrin
Irini Bournazou, … , Adriano G. Rossi, Christopher D. Gregory
Irini Bournazou, … , Adriano G. Rossi, Christopher D. Gregory
Published December 1, 2008
Citation Information: J Clin Invest. 2009;119(1):20-32. https://doi.org/10.1172/JCI36226.
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Research Article Immunology

Apoptotic human cells inhibit migration of granulocytes via release of lactoferrin

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Abstract

Apoptosis is a noninflammatory, programmed form of cell death. One mechanism underlying the non-phlogistic nature of the apoptosis program is the swift phagocytosis of the dying cells. How apoptotic cells attract mononuclear phagocytes and not granulocytes, the professional phagocytes that accumulate at sites of inflammation, has not been determined. Here, we show that apoptotic human cell lines of diverse lineages synthesize and secrete lactoferrin, a pleiotropic glycoprotein with known antiinflammatory properties. We further demonstrated that lactoferrin selectively inhibited migration of granulocytes but not mononuclear phagocytes, both in vitro and in vivo. Finally, we were able to attribute this antiinflammatory function of lactoferrin to its effects on granulocyte signaling pathways that regulate cell adhesion and motility. Together, our results identify lactoferrin as an antiinflammatory component of the apoptosis milieu and define what we believe to be a novel antiinflammatory property of lactoferrin: the ability to function as a negative regulator of granulocyte migration.

Authors

Irini Bournazou, John D. Pound, Rodger Duffin, Stylianos Bournazos, Lynsey A. Melville, Simon B. Brown, Adriano G. Rossi, Christopher D. Gregory

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Figure 3

Lactoferrin specifically inhibits neutrophil chemotaxis.

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Lactoferrin specifically inhibits neutrophil chemotaxis.
Neutrophil chem...
Neutrophil chemotaxis in the presence of human anti-lactoferrin (anti-LTF) polyclonal antibody (gray) or isotype control (black) using conditioned media from BL (A) and MCF7 (B) cells (A: n = 3, *P < 0.05 vs. isotype control, NS vs. fMLP anti-lactoferrin control; B; n = 3, †P < 0.001 vs. fMLP/isotype; NS vs. fMLP/anti-LTF. (C) RT-PCR analysis to assess lactoferrin expression in BL cells stably expressing LTF shRNA (LTF) cells and mock-transfected (mm) cells induced to become apoptotic (1 μM staurosporine; 37°C). (D) Chemotaxis assay to determine neutrophil migration toward supernatants obtained from control, LTF shRNA, and mock-transfected BL cells (n = 5; §P < 0.05 compared with mm shRNA control; **P < 0.05 compared with fMLP; NS compared with fMLP control). (E) Dose-response analysis of purified human lactoferrin. n = 3; ¶P < 0.05 vs. 0 g/ml purified LTF + fMLP. Error bars indicate SEM.

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