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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2252-2261.
Prepublished online as a Blood First Edition Paper on November 29, 2005; DOI 10.1182/blood-2005-05-2011.


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CHEMOKINES, CYTOKINES, AND INTERLEUKINS

Migration inhibitory factor up-regulates vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 via Src, PI3 kinase, and NF{kappa}B

M. Asif Amin, Christian S. Haas, Kui Zhu, Pamela J. Mansfield, Michael J. Kim, Nicholas P. Lackowski, and Alisa E. Koch

From the Department of Medicine, University of Michigan Medical School, Ann Arbor; the Department of Medicine, Northwestern University Medical School, Chicago, IL; the Veterans Administration Chicago Health Care Medical Center, Lakeside Division, Chicago, IL; and the Veterans Administration, Ann Arbor, MI.

Cell adhesion molecules are critical in monocyte (MN) recruitment in immune-mediated and hematologic diseases. We investigated the novel role of recombinant human migration inhibitory factor (rhMIF) in up-regulating vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) and their signaling pathways in human MNs. rhMIF-induced expression of VCAM-1 and ICAM-1 was significantly higher compared with nonstimulated MNs. rhMIF induced MN VCAM-1 and ICAM-1 expression in a concentration-dependent manner (P < .05). Antisense oligodeoxynucleotides (ODNs) and inhibitors of Src, PI3K, p38, and NF{kappa}B significantly reduced rhMIF-induced MN VCAM-1 and ICAM-1 expression (P < .05). However, Erk1/2 and Jak2 were not involved. Silencing RNA directed against MIF, and inhibitors of Src, PI3K, NF{kappa}B, anti–VCAM-1, and anti–ICAM-1 significantly inhibited rhMIF-induced adhesion of HL-60 cells to human dermal microvascular endothelial cells (HMVECs) or an endothelial cell line, HMEC-1, in cell adhesion assays, suggesting the functional significance of MIF-induced adhesion molecules (P < .05). rhMIF also activated MN phospho-Src, -Akt, and -NF{kappa}B in a time-dependent manner. rhMIF induced VCAM-1 and ICAM-1 up-regulation in 12 hours via Src, PI3K, and NF{kappa}B as shown by Western blotting and immunofluorescence. MIF and MIF-dependent signaling pathways may be a potential target for treating diseases characterized by up-regulation of cell adhesion molecules.


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