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Blood, 15 January 2005, Vol. 105, No. 2, pp. 464-473.
Prepublished online as a Blood First Edition Paper on September 28, 2004; DOI 10.1182/blood-2003-12-4415.
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Submitted December 29, 2003
Accepted September 7, 2004
IL-8 and its CXCR1 and CXCR2 receptors participate in the control of megakaryocytic proliferation, differentiation and ploidy in myeloid metaplasia with myelofibrosis
Sharareh Emadi, Denis Clay, Christophe Desterke, Bernadette Guertron, Eliane Maquarre, Agnes Charpentier, Claude Jasmin, and Marie-Caroline Le Bousse-Kerdiles*
Unite 602, Andre Lwoff Institute, Paul Brousse Hospital, Institut National de la Sante et de la Recherche Medicale (Inserm), Villejuif, France; Department of Chemical and Material Engineering (CME), Arizona State University, Tempe, AZ, USA
Unite 602, Andre Lwoff Institute, Paul Brousse Hospital, Institut National de la Sante et de la Recherche Medicale (Inserm), Villejuif, France
Laboratory of Hematology, Saint-Vincent Hospital, Groupe Hospitalier de l'Institut Catholique de Lille, Lille Cedex, France
* Corresponding author; email: lebousse{at}vjf.inserm.fr.
Myeloproliferation, myelofibrosis and neo-angiogenesis are the three major intrinsic pathophysiological features of Myeloid Metaplasia with Myelofibrosis (MMM). The myeloproliferation is characterized by an increased number of circulating CD34+ progenitors with the prominent amplification of dystrophic megakaryocytic (MK) cells and myeloid metaplasia in the spleen and liver. The various biological activities of IL-8 in haematopoietic progenitor proliferation and mobilisation as well as in neoangiogenesis prompted us to analyse its potential role in MMM. We showed that the level of IL8 chemokine is significantly increased in the serum of patients and that various hematopoietic cells including platelets participate in its production. In vitro inhibition of autocrine IL-8 expressed by CD34+ cells with either a neutralising or an antisense anti-IL-8 treatment increases the proliferation of MMM CD34+ derived cells and stimulates their MK differentiation. Moreover, addition of neutralising anti-IL-8 receptor (CXCR1 or CXCR2) antibodies to MMM CD34+ cells cultured under MK liquid culture conditions increases the proliferation and differentiation of MMM CD41+ MK cells and restores their polyploidization. Our results suggest that IL-8 and its receptors participate in the altered MK growth that features MMM and open new therapeutic prospects for this still incurable disease.
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