Platelet factor 4 promotes adhesion of hematopoietic progenitor cells and binds IL-8: Novel mechanisms for modulation of hematopoiesis

Arkadiusz Z Dudek, Irina Nesmelova, Kevin Mayo, Catherine M. Verfaillie, Simon Pitchford, Arne Slungaard

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

Platelet factor 4 (PF4) is an abundant platelet α-granule C-X-C chemokine that has weak chemotactic potency but strongly inhibits hematopoiesis through an unknown mechanism. We find that PF4 binds to human CD34+ hematopoietic progenitor cells (HPCs) with a median effective concentration of 1 μg/mL but not after exposure to chondroitinase ABC. PF4 enhances adhesion of HPCs to intact stroma. Committed progenitors also adhere avidly to immobilized PF4. This adhesion is time-dependent, requires metabolic activity, causes cytoskeletal rearrangement, and induces cell-cycle inhibition. Using extracellular acidification rate to indicate transmembrane signaling, we find that interleukin-8 (IL-8), but not PF4, activates CD34+ progenitors, and PF4 blocks IL-8-mediated activation. Surface plasmon resonance analysis shows that PF4 binds IL-8 with high (dissociation constant [Kd] = 42 nM) affinity. Nuclear magnetic resonance analysis of IL-8 and PF4 in solution confirms this interaction. We conclude that PF4 has the capacity to influence hematopoiesis through mechanisms not mediated by a classical high-affinity, 7-transmembrane domain chemokine receptor. Instead, PF4 may modulate the hematopoietic milieu both directly, by promoting progenitor adhesion and quiescence through interaction with an HPC chondroitin sulfate-containing moiety, and indirectly, by binding to or interfering with signaling caused by other, hematopoietically active chemokines, such as IL-8.

Original languageEnglish (US)
Pages (from-to)4687-4694
Number of pages8
JournalBlood
Volume101
Issue number12
DOIs
StatePublished - Jun 15 2003

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