Leukotriene B4, an activation product of mast cells, is a chemoattractant for their progenitors

Abstract

Mast cells are tissue-resident cells with important functions in allergy and inflammation. Pluripotential hematopoietic stem cells in the bone marrow give rise to committed mast cell progenitors that transit via the blood to tissues throughout the body, where they mature. Knowledge is limited about the factors that release mast cell progenitors from the bone marrow or recruit them to remote tissues. Mouse femoral bone marrow cells were cultured with IL-3 for 2 wk and a range of chemotactic agents were tested on the c-kit+ population. Cells were remarkably refractory and no chemotaxis was induced by any chemokines tested. However, supernatants from activated mature mast cells induced pronounced chemotaxis, with the active principle identified as leukotriene (LT) B4. Other activation products were inactive. LTB4 was highly chemotactic for 2-wk-old cells, but not mature cells, correlating with a loss of mRNA for the LTB4 receptor, BLT1. Immature cells also accumulated in vivo in response to intradermally injected LTB4. Furthermore, LTB4 was highly potent in attracting mast cell progenitors from freshly isolated bone marrow cell suspensions. Finally, LTB4 was a potent chemoattractant for human cord blood–derived immature, but not mature, mast cells. These results suggest an autocrine role for LTB4 in regulating tissue mast cell numbers.

Chemotactic action of prostaglandin E2on mouse mast cells acting via the PGE2receptor 3

“…This is consistent with previous observations of mast cell markers (14,20). The apparently greater response of the 10-wk BMMC to PGE 2 may be explained by the higher percentage of c-kit ϩ cells in the 10-wk cultures (20); after 2 wk in culture, Ϸ40% total cells were c-kit ϩ , whereas after 10 wk in culture, Ͼ95% total cells were c-kit ϩ . Taking this into account, PGE 2 has equal efficacy for 2-and 10-wk BMMC.…”

“…It is of interest that the chemoattractant produced by challenged/sensitized mucosal tissue, described here, is different from that detected in supernatants from challenged/sensitized mast cells in isolation (20). This could result from a phenotypic difference between the in situ and cultured mast cells involved.…”

“…Because LTB 4 is produced by mature mast cells on activation, these observations provide a potential mechanism contributing to mast cell hyperplasia in allergic reactions (20). The current study suggests that other eicosanoids may be involved in mast cell migration in vivo but perhaps at a different stage in the life history of the cell.…”

“…In a previous study (20), we showed that mast cell receptor ␣, ␤, and ␥ isoforms in 2-wk BMMC were analyzed by RT-PCR and compared with the housekeeping gene GAPDH. The 400-bp PCR product for the ␤ isoform was sequenced and confirmed as EP3 receptor ␤, and the additional 500-bp PCR product was sequenced and determined to be EP3 receptor ␣ product.…”

“…We recently showed that leukotriene B 4 (LTB 4 ), signaling via the BLT1 receptor, is a potent chemoattractant for murine and human immature but not mature mast cells (20). Because LTB 4 is produced by mature mast cells on activation, these observations provide a potential mechanism contributing to mast cell hyperplasia in allergic reactions (20).…”