Search tips
Search criteria 


Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Exp Med. 1992 January 1; 175(1): 237–244.
PMCID: PMC2119079

c-kit ligand: a unique potentiator of mediator release by human lung mast cells


Mast cells (MC) play a central role in extrinsic allergic reactions such as asthma and may participate in other inflammatory and fibrotic processes. However, with the exception of immunoglobulin E (IgE) receptor-dependent stimulation, no secretagogues of human lung MC have yet been described. It is also unclear whether mediator release can be regulated by certain cytokines as demonstrated previously in basophils and other human inflammatory effector cells. Here, we show that the c- kit ligand (KL), a recently identified stem cell growth factor, at concentrations 10-100 times lower than that required to promote cell proliferation, enhances the release of histamine and leukotriene C4 in response to IgE receptor crosslinking of human lung MC. KL does not induce mediator release per se, but increases the sensitivity of MC to anti-IgE receptor stimulation and also enhances mediator release to maximally effective concentrations of anti-IgE receptor antibody. By contrast, a large number of cytokines examined, including the mast cell growth factors/agonists in rodents, interleukin 3 (IL-3), IL-4, IL-9, and nerve growth factor, were ineffective in this respect. These findings suggest a unique role of KL in regulating effector functions of human mucosal MC.

Full Text

The Full Text of this article is available as a PDF (826K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Schleimer RP, Fox CC, Naclerio RM, Plaut M, Creticos PS, Togias AG, Warner JA, Kagey-Sobotka A, Lichtenstein LM. Role of human basophils and mast cells in the pathogenesis of allergic diseases. J Allergy Clin Immunol. 1985 Aug;76(2 Pt 2):369–374. [PubMed]
  • MacGlashan DW, Jr, Schleimer RP, Peters SP, Schulman ES, Adams GK, Sobotka AK, Newball HH, Lichtenstein LM. Comparative studies of human basophils and mast cells. Fed Proc. 1983 May 15;42(8):2504–2509. [PubMed]
  • Stevens RL, Austen KF. Recent advances in the cellular and molecular biology of mast cells. Immunol Today. 1989 Nov;10(11):381–386. [PubMed]
  • Rothe MJ, Nowak M, Kerdel FA. The mast cell in health and disease. J Am Acad Dermatol. 1990 Oct;23(4 Pt 1):615–624. [PubMed]
  • Wodnar-Filipowicz A, Heusser CH, Moroni C. Production of the haemopoietic growth factors GM-CSF and interleukin-3 by mast cells in response to IgE receptor-mediated activation. Nature. 1989 May 11;339(6220):150–152. [PubMed]
  • Bienenstock J, Tomioka M, Matsuda H, Stead RH, Quinonez G, Simon GT, Coughlin MD, Denburg JA. The role of mast cells in inflammatory processes: evidence for nerve/mast cell interactions. Int Arch Allergy Appl Immunol. 1987;82(3-4):238–243. [PubMed]
  • Benyon RC, Lowman MA, Church MK. Human skin mast cells: their dispersion, purification, and secretory characterization. J Immunol. 1987 Feb 1;138(3):861–867. [PubMed]
  • Schulman ES, Post TJ, Henson PM, Giclas PC. Differential effects of the complement peptides, C5a and C5a des Arg on human basophil and lung mast cell histamine release. J Clin Invest. 1988 Mar;81(3):918–923. [PMC free article] [PubMed]
  • Dahinden CA, Zingg J, Maly FE, de Weck AL. Leukotriene production in human neutrophils primed by recombinant human granulocyte/macrophage colony-stimulating factor and stimulated with the complement component C5A and FMLP as second signals. J Exp Med. 1988 Apr 1;167(4):1281–1295. [PMC free article] [PubMed]
  • Fujisawa T, Abu-Ghazaleh R, Kita H, Sanderson CJ, Gleich GJ. Regulatory effect of cytokines on eosinophil degranulation. J Immunol. 1990 Jan 15;144(2):642–646. [PubMed]
  • Takafuji S, Bischoff SC, De Weck AL, Dahinden CA. IL-3 and IL-5 prime normal human eosinophils to produce leukotriene C4 in response to soluble agonists. J Immunol. 1991 Dec 1;147(11):3855–3861. [PubMed]
  • Hirai K, Morita Y, Misaki Y, Ohta K, Takaishi T, Suzuki S, Motoyoshi K, Miyamoto T. Modulation of human basophil histamine release by hemopoietic growth factors. J Immunol. 1988 Dec 1;141(11):3958–3964. [PubMed]
  • Kurimoto Y, De Weck AL, Dahinden CA. The effect of interleukin 3 upon IgE-dependent and IgE-independent basophil degranulation and leukotriene generation. Eur J Immunol. 1991 Feb;21(2):361–368. [PubMed]
  • Kurimoto Y, de Weck AL, Dahinden CA. Interleukin 3-dependent mediator release in basophils triggered by C5a. J Exp Med. 1989 Aug 1;170(2):467–479. [PMC free article] [PubMed]
  • Bischoff SC, Brunner T, De Weck AL, Dahinden CA. Interleukin 5 modifies histamine release and leukotriene generation by human basophils in response to diverse agonists. J Exp Med. 1990 Dec 1;172(6):1577–1582. [PMC free article] [PubMed]
  • Pearce FL, Thompson HL. Some characteristics of histamine secretion from rat peritoneal mast cells stimulated with nerve growth factor. J Physiol. 1986 Mar;372:379–393. [PubMed]
  • Witte ON. Steel locus defines new multipotent growth factor. Cell. 1990 Oct 5;63(1):5–6. [PubMed]
  • Martin FH, Suggs SV, Langley KE, Lu HS, Ting J, Okino KH, Morris CF, McNiece IK, Jacobsen FW, Mendiaz EA, et al. Primary structure and functional expression of rat and human stem cell factor DNAs. Cell. 1990 Oct 5;63(1):203–211. [PubMed]
  • Bernstein ID, Andrews RG, Zsebo KM. Recombinant human stem cell factor enhances the formation of colonies by CD34+ and CD34+lin- cells, and the generation of colony-forming cell progeny from CD34+lin- cells cultured with interleukin-3, granulocyte colony-stimulating factor, or granulocyte-macrophage colony-stimulating factor. Blood. 1991 Jun 1;77(11):2316–2321. [PubMed]
  • Broxmeyer HE, Cooper S, Lu L, Hangoc G, Anderson D, Cosman D, Lyman SD, Williams DE. Effect of murine mast cell growth factor (c-kit proto-oncogene ligand) on colony formation by human marrow hematopoietic progenitor cells. Blood. 1991 May 15;77(10):2142–2149. [PubMed]
  • Schulman ES, MacGlashan DW, Jr, Peters SP, Schleimer RP, Newball HH, Lichtenstein LM. Human lung mast cells: purification and characterization. J Immunol. 1982 Dec;129(6):2662–2667. [PubMed]
  • Anderson DM, Lyman SD, Baird A, Wignall JM, Eisenman J, Rauch C, March CJ, Boswell HS, Gimpel SD, Cosman D, et al. Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms. Cell. 1990 Oct 5;63(1):235–243. [PubMed]
  • Brunner T, de Weck AL, Dahinden CA. Platelet-activating factor induces mediator release by human basophils primed with IL-3, granulocyte-macrophage colony-stimulating factor, or IL-5. J Immunol. 1991 Jul 1;147(1):237–242. [PubMed]
  • Dahinden CA, Kurimoto Y, De Weck AL, Lindley I, Dewald B, Baggiolini M. The neutrophil-activating peptide NAF/NAP-1 induces histamine and leukotriene release by interleukin 3-primed basophils. J Exp Med. 1989 Nov 1;170(5):1787–1792. [PMC free article] [PubMed]
  • Bischoff SC, de Weck AL, Dahinden CA. Interleukin 3 and granulocyte/macrophage-colony-stimulating factor render human basophils responsive to low concentrations of complement component C3a. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6813–6817. [PubMed]
  • Wasserman SI. Mast cell biology. J Allergy Clin Immunol. 1990 Oct;86(4 Pt 2):590–593. [PubMed]
  • Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, Chen E, Schlessinger J, Francke U, Ullrich A. Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J. 1987 Nov;6(11):3341–3351. [PubMed]
  • Mayrhofer G, Gadd SJ, Spargo LD, Ashman LK. Specificity of a mouse monoclonal antibody raised against acute myeloid leukaemia cells for mast cells in human mucosal and connective tissues. Immunol Cell Biol. 1987 Jun;65(Pt 3):241–250. [PubMed]
  • Ashman LK, Cambareri AC, To LB, Levinsky RJ, Juttner CA. Expression of the YB5.B8 antigen (c-kit proto-oncogene product) in normal human bone marrow. Blood. 1991 Jul 1;78(1):30–37. [PubMed]
  • Schleimer RP, MacGlashan DW, Jr, Peters SP, Pinckard RN, Adkinson NF, Jr, Lichtenstein LM. Characterization of inflammatory mediator release from purified human lung mast cells. Am Rev Respir Dis. 1986 Apr;133(4):614–617. [PubMed]
  • Ishizaka T, Conrad DH, Schulman ES, Sterk AR, Ishizaka K. Biochemical analysis of initial triggering events of IgE-mediated histamine release from human lung mast cells. J Immunol. 1983 May;130(5):2357–2362. [PubMed]
  • Klein R, Jing SQ, Nanduri V, O'Rourke E, Barbacid M. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell. 1991 Apr 5;65(1):189–197. [PubMed]
  • Hempstead BL, Martin-Zanca D, Kaplan DR, Parada LF, Chao MV. High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature. 1991 Apr 25;350(6320):678–683. [PubMed]
  • Kanakura Y, Druker B, Cannistra SA, Furukawa Y, Torimoto Y, Griffin JD. Signal transduction of the human granulocyte-macrophage colony-stimulating factor and interleukin-3 receptors involves tyrosine phosphorylation of a common set of cytoplasmic proteins. Blood. 1990 Aug 15;76(4):706–715. [PubMed]
  • Salari H, Chan-Yeung M. Interleukin-1 potentiates antigen-mediated arachidonic acid metabolite formation in mast cells. Clin Exp Allergy. 1989 Nov;19(6):637–641. [PubMed]
  • Levi-Schaffer F, Austen KF, Caulfield JP, Hein A, Gravallese PM, Stevens RL. Co-culture of human lung-derived mast cells with mouse 3T3 fibroblasts: morphology and IgE-mediated release of histamine, prostaglandin D2, and leukotrienes. J Immunol. 1987 Jul 15;139(2):494–500. [PubMed]
  • Flanagan JG, Leder P. The kit ligand: a cell surface molecule altered in steel mutant fibroblasts. Cell. 1990 Oct 5;63(1):185–194. [PubMed]
  • Huang E, Nocka K, Beier DR, Chu TY, Buck J, Lahm HW, Wellner D, Leder P, Besmer P. The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell. 1990 Oct 5;63(1):225–233. [PubMed]
  • Tsai M, Shih LS, Newlands GF, Takeishi T, Langley KE, Zsebo KM, Miller HR, Geissler EN, Galli SJ. The rat c-kit ligand, stem cell factor, induces the development of connective tissue-type and mucosal mast cells in vivo. Analysis by anatomical distribution, histochemistry, and protease phenotype. J Exp Med. 1991 Jul 1;174(1):125–131. [PMC free article] [PubMed]
  • Valent P, Besemer J, Sillaber C, Butterfield JH, Eher R, Majdic O, Kishi K, Klepetko W, Eckersberger F, Lechner K, et al. Failure to detect IL-3-binding sites on human mast cells. J Immunol. 1990 Nov 15;145(10):3432–3437. [PubMed]
  • Massey WA, Randall TC, Kagey-Sobotka A, Warner JA, MacDonald SM, Gillis S, Allison AC, Lichtenstein LM. Recombinant human IL-1 alpha and -1 beta potentiate IgE-mediated histamine release from human basophils. J Immunol. 1989 Sep 15;143(6):1875–1880. [PubMed]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press