Stem cell factor influences neuro-immune interactions: The response of mast cells to pituitary adenylate cyclase activating polypeptide is altered by stem cell factor

Interactions between products of the mouse W locus, which encodes the c-kit tyrosine kinase receptor, and the Sl locus, which encodes a ligand for c-kit receptor, which we have designated stem cell factor (SCF), have a critical role in the development of mast cells. Mice homozygous for mutations at either locus exhibit several phenotypic abnormalities including a virtual absence of mast cells. Moreover, the c-kit ligand SCF can induce the proliferation and maturation of normal mast cells in vitro or in vivo, and also can result in repair of the mast cell deficiency of Sl/Sld mice in vivo. We now report that administration of SCF intradermally in vivo results in dermal mast cell activation and a mast cell-dependent acute inflammatory response. This effect is c-kit receptor dependent, in that it is not observed when SCF is administered to mice containing dermal mast cells expressing functionally inactive c-kit receptors, is observed with both glycosylated and nonglycosylated forms of SCF, and occurs at doses of SCF at least 10-fold lower on a molar basis than the minimally effective dose of the classical dermal mast cell-activating agent substance P. These findings represent the first demonstration in vivo that a c-kit ligand can result in the functional activation of any cellular lineage expressing the c-kit receptor, and suggest that interactions between the c-kit receptor and its ligand may influence mast cell biology through complex effects on proliferation, maturation, and function.

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Cofactors are essential for stem cell factor-dependent growth and maturation of mast cell progenitors: comparative effects of interleukin- 3 (IL-3), IL-4, IL-10, and fibroblasts

Blood ◽

10.1182/blood.v85.1.57.bloodjournal85157 ◽

1995 ◽

Vol 85 (1) ◽

pp. 57-65 ◽

Cited By ~ 77

Author(s):

D Rennick ◽

B Hunte ◽

G Holland ◽

L Thompson-Snipes

Keyword(s):

Mast Cell ◽

Stem Cell ◽

Cell Differentiation ◽

Mast Cells ◽

Colony Formation ◽

Stem Cell Factor ◽

Interleukin 10 ◽

Interleukin 4 ◽

Phenotypic Change ◽

Interleukin 3

Stem cell factor (SCF) possesses many mast cell-stimulating activities, including the ability to support the growth of mucosal-like mast cells (MMCs) and connective tissue mast cells (CTMCs). However, this study shows that, in the absence of accessory cells, SCF does not stimulate the clonal growth of primitive mast cell progenitors. Nevertheless, SCF exhibited potent growth-promoting effects when combined with the cytokines interleukin-3 (IL-3), interleukin-4 (IL-4), and interleukin- 10 (IL-10). Our comparative studies have shown that optimal mast cell colony formation occurs when both IL-4 and IL-10 are combined with SCF. However, in the presence of SCF, these two cofactors appear to mediate different effects. IL-4 was more efficient than IL-10 in costimulating the initiation of SCF-dependent colony formation by mast cell progenitors and in sustaining the proliferation of newly generated progeny. On the other hand, IL-4 was less efficient than IL-10 in supporting mast cell differentiation, as evidenced by morphology, cell enlargement, and granule production. Although the actions of IL-4 and IL-10 were not equivalent, additional experiments indicated that their ability to serve as early- and late-acting factors, respectively, were complimentary. We have also found that the mast cells generated in colonies stimulated by IL-4, IL-10, and SCF produced high levels of histamine (6–8 pg per cell). None of the mast cells generated in our cultures synthesized heparin. A phenotypic change from safranin- negative to safranin-positive cells associated with heparin-producing CTMCs was accomplished after coculture of the mast cells with fibroblast cell lines derived from normal mice or from SI/SId mice plus soluble factors. Collectively, our observations demonstrate that SCF acts as a competence factor for mast cell progenitor growth. In addition, the ability of SCF to support certain stages of mast cell differentiation is profoundly influenced by interactions with specific cofactors.

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Stem cell factor and interleukin-4 increase responsiveness of mast cells to Substance P

Experimental Hematology ◽

10.1016/s0301-472x(00)00161-2 ◽

2000 ◽

Vol 28 (6) ◽

pp. 626-634 ◽

Cited By ~ 30

Author(s):

Khalil Karimi ◽

Frank A Redegeld ◽

Richard Blom ◽

Frans P Nijkamp

Keyword(s):

Stem Cell ◽

Mast Cells ◽

Substance P ◽

Stem Cell Factor ◽

Interleukin 4

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Stem cell factor-dependent human cord blood derived mast cells express α- and β-tryptase, heparin and chondroitin sulphate

Immunology ◽

10.1111/j.1365-2567.1996.tb00020.x ◽

1996 ◽

Vol 88 (2) ◽

pp. 308-314 ◽

Cited By ~ 34

Author(s):

G. NILSSON ◽

T. BLOM ◽

I. HARVIMA ◽

M. KUSCHE-GULLBERG ◽

K. NILSSON ◽

...

Keyword(s):

Stem Cell ◽

Mast Cells ◽

Cord Blood ◽

Stem Cell Factor ◽

Chondroitin Sulphate ◽

Human Cord Blood

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Eotaxin Modulates Myelopoiesis and Mast Cell Development From Embryonic Hematopoietic Progenitors

Blood ◽

10.1182/blood.v92.6.1887 ◽

1998 ◽

Vol 92 (6) ◽

pp. 1887-1897 ◽

Cited By ~ 43

Author(s):

Elizabeth J. Quackenbush ◽

Barry K. Wershil ◽

Vincent Aguirre ◽

Jose-Carlos Gutierrez-Ramos

Keyword(s):

Mast Cell ◽

Stem Cell ◽

Mast Cells ◽

Stem Cell Factor ◽

Fetal Liver ◽

Hematopoietic Progenitors ◽

Embryonic Tissues ◽

Pathological Conditions ◽

Gi Protein ◽

American Society

Abstract Eotaxin is a potent chemoattractant for eosinophils during inflammation and allergic reactions in the adult, but its role in the embryonic development of the hematopoietic system has not been examined. We report here that eotaxin and its receptor, CCR-3, are expressed by embryonic tissues responsible for blood development, such as fetal liver (FL), yolk sac (YS), and peripheral blood. We found that eotaxin acts synergistically with stem cell factor to accelerate the differentiation of embryonic mast cell progenitors, and this response can be suppressed by pertussis toxin, an inhibitor of chemokine-induced signaling through Gi protein and chemotaxis. Eotaxin promotes the differentiation of fetal mast cell progenitors into differentiated mast cells as defined by the expression of mast cell specific proteases. Furthermore, in combination with stem cell factor (SCF), it promotes the growth of Mac-1+myeloid cells from embryonic progenitors. These studies suggest that eotaxin may be involved in the growth of granulocytic progenitors and the differentiation and/or function of mast cells during embryogenesis and/or pathological conditions that induce high levels of eotaxin, such as allergic responses. © 1998 by The American Society of Hematology.

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