Retinoic Acid Inhibits in vitro Development of Mast Cells But Has No Marked Effect on Mature Human Skin Tryptase- and Chymase-Positive Mast Cells

Abstract

Stem cell factor plays a key role in the development of human mast cells via interaction with Kit receptor. We and other groups have previously shown that a number of cytokines can regulate the stem-cell-factor-dependent development of mast cells in vitro. In this study we investigated the effect of retinoic acid on human mast cells in vitro and in vivo. Retinoids are known to have strong modulatory effects on hematopoietic differentiation. We found that all-trans-retinoic acid, at concentrations as low as 1 nM, inhibits the stem-cell-factor-dependent differentiation of mast cells in vitro. This effect of retinoic acid was found to be on progenitor cells, whereas more mature mast cells were less affected. The use of specific agonists binding either to the RAR or the RXR nuclear receptors indicated involvement of both the RAR/RXR and RXR/RXR pathways in inhibiting mast cell differentiation. In contrast to the effects on mast cell progenitors, retinoic acid had no effect on the number of mature mast cells in skin organ cultures. Furthermore, topical treatment of normal skin with a retinoic-acid-containing cream caused an increase in the number of tryptase-positive mast cells, whereas the numbers of the major cutaneous mast cell type, tryptase- and chymase-positive mast cells, remained unaffected. Our results suggest that retinoic acid suppresses commitment of progenitor cells into the mast cell lineage and/or acts on early mast cell progenitors, whereas mature cutaneous mast cells are less susceptible to retinoic acid.

Retinoic Acid Negatively Impacts Proliferation and MCTC Specific Attributes of Human Skin Derived Mast Cells, but Reinforces Allergic Stimulability

“…Together, this implies that the mechanisms by which RA inhibits mitogenesis are cell-type specific. The anti-proliferative activity detected here for non-transformed skin-derived MCs is consistent with RA-induced cell cycle arrest in leukemia cells, including cells of the human MC line HMC-1 [47,48], as well as in hematopoietic progenitor-derived MCs [43,44]. The combined evidence now indicates that RA interference with MC proliferation occurs in a manner that is largely independent of the precise nature of the MCs (leukemic versus normal, slowly or rapidly dividing, tissue or precursor-derived).…”

“…Collectively, in cycling MCs, RA will counter cell increments by decelerating cell cycle progression, while under conditions in which no (major) proliferation occurs, the MC compartment will unlikely experience major numerical changes by RA, or else survival will even be enhanced, as was also evidenced in a previous study [44]. …”

“…It therefore came as a surprise that a cell, which had received fairly little attention with regard to the cutaneous Vitamin A system, turned out a more important partaker than envisaged thus far [28]. This fostered our interest in the impact imposed by RA on MCs in human skin, complementing earlier reports on RA’s modulation of adhesion molecules and selected differentiation markers, performed chiefly on immature MC lines and in vitro generated MC progenitors [37,41,42,43,44]. …”

“…Moreover, studies that did focus on the retinoid-MC connection rarely employed MCs of skin origin [37,41,42,43,44]. However, MC heterogeneity is a well-known phenomenon, where representatives of the lineage display variability across species, tissues, and microenvironments.…”

Localized Th1-, Th2-, T Regulatory Cell-, and Inflammation-Associated Hepatic and Pulmonary Immune Responses inAscaris suum-Infected Swine Are Increased by Retinoic Acid

“…In addition, intestinal mucosal mast cells increased following exposure to A. suum and released histamine after exposure to parasite-derived antigens via antibody-dependent cross-linking of surface receptors (3). Other investigators have shown that topically applied ATRA increased the number of tryptasepositive mast cells in the skin but had no effect on tryptase-and chymase-double-positive mast cells (19).…”