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Published online before print May 22, 2003

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© 2003 by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0103004

Received for publication January 7, 2003.
Revised March 28, 2003.
Accepted for publication April 3, 2003.

Article

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF- promote the NF-B-dependent maturation of normal and leukemic myeloid cells

Paola Secchiero ^*@, Daniela Milani ^*, Arianna Gonelli ^*, Elisabetta Melloni , Diana Campioni , Davide Gibellini , Silvano Capitani ^*, and Giorgio Zauli

Departments of *Morphology and Embryology, Human Anatomy Section, and Biomedical Sciences and Advanced Therapies, Hematology Section, St. Anna Hospital, University of Ferrara, Italy; Department of Human Normal Morphology, University of Trieste, Italy; and Department of Experimental and Clinical Medicine, Microbiology Section, University of Bologna, St. Orsola Hospital, Italy

^@ To whom correspondence should be addressed. E-mail: secchier{at}mail.umbi.umd.edu.

	Abstract

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF- induced monocytic maturation of primary, normal CD34-derived myeloid precursors and of the M2/M3-type acute myeloid leukemia HL-60 cell line, associated to increased nuclear factor (NF)-B activity and nuclear translocation of p75, p65, and p50 NF-B family members. Consistently, both cytokines also induced the degradation of the NF-B inhibitors, IB and IB, and up-regulated the surface expression of TRAIL-R3, a known NF-B target. However, NF-B activation and IB degradation occurred with different time-courses, and TNF- was more potent, rapid, and transient than TRAIL. Of the two TRAIL receptors constitutively expressed by HL-60 (TRAIL-R1 and TRAIL-R2), only the former was involved in IB degradation, as demonstrated by using agonistic anti-TRAIL receptor antibodies. Moreover, NF-B nuclear translocation induced by TRAIL but not by TNF- was abrogated by z-IETD-fmk, a caspase-8-specific inhibitor. The key role of NF-B in mediating the biological effects of TNF- and TRAIL was demonstrated by the ability of unrelated pharmacological inhibitors of the NF-B pathway (parthenolide and MG-132) to abrogate TNF-- and TRAIL-induced monocytic maturation. These findings demonstrate that NF-B is essential for monocytic maturation and is activated via distinct pathways, involving or not involving caspases, by the related cytokines TRAIL and TNF-.

Key Words: IB • Fas-associated death domain • human monocyte-associated esterase-1

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