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Chemokine regulation of human megakaryocytopoiesis
AM Gewirtz, J Zhang, J Ratajczak, M Ratajczak, KS Park, C Li, Z Yan and M Poncz
Department of Pathology, University of Pennsylvania School of Medicine,
Philadelphia, USA.
We have previously shown that platelet factor 4 (PF4), a platelet- specific
CXC chemokine, can directly and specifically inhibit human megakaryocyte
colony formation. We therefore hypothesized that PF4 might function as a
negative autocrine regulator of megakaryocytopoiesis. Herein we present
additional studies characterizing the inhibitory effect of CXC chemokines
on human megakaryocyte development. We first corroborated our initial
studies by showing that recombinant human (rH) PF4, like the native
protein, inhibited megakaryocytopoiesis. We then examined the inhibitory
properties of other CXC family members. Neutrophil activating peptide-2
(NAP-2), a naturally occurring N-terminally cleaved beta TG peptide, was
found to inhibit megakaryocytopoiesis with two to three orders of magnitude
greater potency than PF4. Structure function studies showed that an
N-terminal mutation, which eliminated NAP-2's neutrophil activating
properties (NAP-2E2-->A), also abrogated its ability to inhibit
megakaryocyte development. Further investigations of this type demonstrated
that a chimeric PF4 protein (AELR/PF4) in which PF4's N- terminus was
replaced with the first four amino acids of NAP-2 was also a potent
inhibitor of megakaryocytopoiesis. Interleukin (IL)-8, another CXC
chemokine, and three CC chemokines (macrophage inhibitory protein-1 alpha
[MIP-1 alpha], MIP-1 beta, and C10) also specifically inhibited
megakaryocyte colony formation at NAP-2 equivalent doses. CXC and CC
chemokine inhibition was additive suggesting that the effects might be
mediated through a common pathway. The inhibitory effects of NAP-2 and
MIP-1 alpha could not be overcome by adding physiologically relevant
amounts of recombinant human megakaryocyte growth and development factor
(MGDR) (50 ng/mL) to the cultures. Using Northern blot and reverse
transcriptase-polymerase chain reaction (RT-PCR) based analyses, we
documented mRNA expression of IL-8 receptor isoforms alpha and beta in
total platelet RNA and in normal human megakaryocytes, respectively. Based
on these results, we hypothesize that chemokines play a physiologic role in
regulating megakaryocytopoiesis. Because chemokines are elaborated by
ancillary marrow cells, both autocrine and paracrine growth control is
suggested, the effects of which might be exerted, in part, through alpha
and beta IL-8 receptors.
Volume 86,
Issue 7,
pp. 2559-2567,
10/01/1995
Copyright © 1995 by The American Society of Hematology
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