Chemotaxis and transendothelial migration of CD34(+) hematopoietic progenitor cells induced by the inflammatory mediator leukotriene D4 are mediated by the 7-transmembrane receptor CysLT1

Recent studies suggest that bone marrow (BM)-derived chemotactic mediators such as chemokines play key roles in hematopoietic stem cell trafficking. L ipid mediators, particularly leukotrienes, are involved in leukocyte chemot axis during inflammation but have also been detected in the normal BM. Ther efore, the effects of leukotrienes on hematopoietic progenitor cells were a nalyzed. Cysteinyl leukotrienes, particularly leukotriene D4 (LTD4), induce d strong intracellular calcium fluxes and actin polymerization in mobilized and BM CD34(+) progenitors. Chemotaxis and in vitro transendothelial migra tion of CD34(+) and more primitive CD34(+)/CD38(-) cells were P-fold increa sed by LTD4 at an optimum concentration of 25 to 50 nM, Accordingly, CD34() cells expressed the 7-transmembrane LTD4 receptor CysLT1 by reverse trans criptase-polymerase chain reaction and Western blot. Effects of LTD4 were s uppressed by the CysLT1 receptor antagonist MK-571 and reduced by pertussis toxin. In contrast, LTB4 induced strong responses only in mature granulocy tes, LTD4-induced calcium fluxes were also observed in granulocytes but wer e not reduced by MK-571, suggesting that these effects were mediated by oth er receptors (eg, CysLT2) rather than by CysLT1. In addition, expression of 5-lipoxygenase, the key enzyme of leukotriene biosynthesis, was detected i n both hematopoietic progenitor cells and mature leukocytes. The study conc ludes that the functionally active LTD4 receptor CysLT1 is preferentially e xpressed in immature hematopoietic progenitor cells. LTD4 released in the B M might regulate progenitor cell trafficking and could also act as an autoc rine mediator of hematopoiesis, This would be a first physiologic effect of cysteinyl leukotrienes apart from the many known pathophysiologic actions related to allergy and inflammation. (Blood. 2001;97:3433-3440) (C) 2001 by The American Society of Hematology.