• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Jun 15, 1997; 99(12): 3009–3017.
PMCID: PMC508153

Granulocyte macrophage colony-stimulating factor is overproduced by keratinocytes in atopic dermatitis. Implications for sustained dendritic cell activation in the skin.

Abstract

Lesional skin of atopic dermatitis (AD) harbors high numbers of dendritic cells with enhanced stimulatory capacity for T lymphocytes. In this study, lesional AD skin was shown to stain heavily in both epidermal and dermal compartments for GM-CSF, a cytokine crucial to dendritic cell functions. Keratinocyte cultures established from uninvolved skin of AD patients exhibited markedly increased spontaneous and PMA-stimulated release of GM-CSF compared with keratinocytes from nonatopic controls. Correspondingly, keratinocytes from AD patients showed higher constitutive as well as PMA-induced GM-CSF gene expression. Larger amounts of GM-CSF were produced by AD keratinocytes, also in response to IL-1alpha, but not after stimulation with LPS, lipoteichoic acid, or staphylococcal enterotoxin B. Hydrocortisone reduced GM-CSF gene expression and protein release in both atopic and control keratinocytes. Supernatants from atopic keratinocytes were able to strongly stimulate PBMC proliferation in a GM-CSF-dependent manner. Moreover, conditioned medium from PMA-treated AD keratinocytes, together with exogenous IL-4, could support phenotypical and functional maturation of peripheral blood precursors into dendritic cells. Enhanced production of GM-CSF by keratinocytes may contribute relevantly to the establishment and chronicity of AD lesions, in particular to the increased number, sustained activation, and enhanced antigen-presenting functions of dendritic cells.

Full Text

The Full Text of this article is available as a PDF (403K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Leung DY. Atopic dermatitis: the skin as a window into the pathogenesis of chronic allergic diseases. J Allergy Clin Immunol. 1995 Sep;96(3):302–319. [PubMed]
  • Bos JD, van Garderen ID, Krieg SR, Poulter LW. Different in situ distribution patterns of dendritic cells having Langerhans (T6+) and interdigitating (RFD1+) cell immunophenotype in psoriasis, atopic dermatitis, and other inflammatory dermatoses. J Invest Dermatol. 1986 Sep;87(3):358–361. [PubMed]
  • Bieber T, Ring J, Braun-Falco O. Comparison of different methods for enumeration of Langerhans cells in vertical cryosections of human skin. Br J Dermatol. 1988 Mar;118(3):385–392. [PubMed]
  • Taylor RS, Baadsgaard O, Hammerberg C, Cooper KD. Hyperstimulatory CD1a+CD1b+CD36+ Langerhans cells are responsible for increased autologous T lymphocyte reactivity to lesional epidermal cells of patients with atopic dermatitis. J Immunol. 1991 Dec 1;147(11):3794–3802. [PubMed]
  • Wollenberg A, Kraft S, Hanau D, Bieber T. Immunomorphological and ultrastructural characterization of Langerhans cells and a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema. J Invest Dermatol. 1996 Mar;106(3):446–453. [PubMed]
  • Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–296. [PubMed]
  • Klubal R, Osterhoff B, Wang B, Kinet JP, Maurer D, Stingl G. The high-affinity receptor for IgE is the predominant IgE-binding structure in lesional skin of atopic dermatitis patients. J Invest Dermatol. 1997 Mar;108(3):336–342. [PubMed]
  • Mudde GC, Van Reijsen FC, Boland GJ, de Gast GC, Bruijnzeel PL, Bruijnzeel-Koomen CA. Allergen presentation by epidermal Langerhans' cells from patients with atopic dermatitis is mediated by IgE. Immunology. 1990 Mar;69(3):335–341. [PMC free article] [PubMed]
  • Bellini A, Vittori E, Marini M, Ackerman V, Mattoli S. Intraepithelial dendritic cells and selective activation of Th2-like lymphocytes in patients with atopic asthma. Chest. 1993 Apr;103(4):997–1005. [PubMed]
  • Möller GM, Overbeek SE, Van Helden-Meeuwsen CG, Van Haarst JM, Prens EP, Mulder PG, Postma DS, Hoogsteden HC. Increased numbers of dendritic cells in the bronchial mucosa of atopic asthmatic patients: downregulation by inhaled corticosteroids. Clin Exp Allergy. 1996 May;26(5):517–524. [PubMed]
  • Hamid Q, Boguniewicz M, Leung DY. Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J Clin Invest. 1994 Aug;94(2):870–876. [PMC free article] [PubMed]
  • Pastore S, Cavani A, Girolomoni G. Epidermal cytokine and neuronal peptide modulation of contact hypersensitivity reactions. Immunopharmacology. 1996 Mar;31(2-3):117–130. [PubMed]
  • Wood LC, Elias PM, Calhoun C, Tsai JC, Grunfeld C, Feingold KR. Barrier disruption stimulates interleukin-1 alpha expression and release from a pre-formed pool in murine epidermis. J Invest Dermatol. 1996 Mar;106(3):397–403. [PubMed]
  • Stallcup MR, Washington LD. Region-specific initiation of mouse mammary tumor virus RNA synthesis by endogenous RNA polymerase II in preparations of cell nuclei. J Biol Chem. 1983 Mar 10;258(5):2802–2807. [PubMed]
  • Wang AM, Doyle MV, Mark DF. Quantitation of mRNA by the polymerase chain reaction. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9717–9721. [PMC free article] [PubMed]
  • Feinberg AP, Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. [PubMed]
  • Wong GG, Witek JS, Temple PA, Wilkens KM, Leary AC, Luxenberg DP, Jones SS, Brown EL, Kay RM, Orr EC, et al. Human GM-CSF: molecular cloning of the complementary DNA and purification of the natural and recombinant proteins. Science. 1985 May 17;228(4701):810–815. [PubMed]
  • Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med. 1994 Apr 1;179(4):1109–1118. [PMC free article] [PubMed]
  • Bratton DL, Hamid Q, Boguniewicz M, Doherty DE, Kailey JM, Leung DY. Granulocyte macrophage colony-stimulating factor contributes to enhanced monocyte survival in chronic atopic dermatitis. J Clin Invest. 1995 Jan;95(1):211–218. [PMC free article] [PubMed]
  • Kupper TS, Lee F, Birchall N, Clark S, Dower S. Interleukin 1 binds to specific receptors on human keratinocytes and induces granulocyte macrophage colony-stimulating factor mRNA and protein. A potential autocrine role for interleukin 1 in epidermis. J Clin Invest. 1988 Nov;82(5):1787–1792. [PMC free article] [PubMed]
  • Tokura Y, Yagi J, O'Malley M, Lewis JM, Takigawa M, Edelson RL, Tigelaar RE. Superantigenic staphylococcal exotoxins induce T-cell proliferation in the presence of Langerhans cells or class II-bearing keratinocytes and stimulate keratinocytes to produce T-cell-activating cytokines. J Invest Dermatol. 1994 Jan;102(1):31–38. [PubMed]
  • Arai KI, Lee F, Miyajima A, Miyatake S, Arai N, Yokota T. Cytokines: coordinators of immune and inflammatory responses. Annu Rev Biochem. 1990;59:783–836. [PubMed]
  • Wood LC, Jackson SM, Elias PM, Grunfeld C, Feingold KR. Cutaneous barrier perturbation stimulates cytokine production in the epidermis of mice. J Clin Invest. 1992 Aug;90(2):482–487. [PMC free article] [PubMed]
  • Nickoloff BJ, Naidu Y. Perturbation of epidermal barrier function correlates with initiation of cytokine cascade in human skin. J Am Acad Dermatol. 1994 Apr;30(4):535–546. [PubMed]
  • Nakamura Y, Ozaki T, Kamei T, Kawaji K, Banno K, Miki S, Fujisawa K, Yasuoka S, Ogura T. Increased granulocyte/macrophage colony-stimulating factor production by mononuclear cells from peripheral blood of patients with bronchial asthma. Am Rev Respir Dis. 1993 Jan;147(1):87–91. [PubMed]
  • Till S, Li B, Durham S, Humbert M, Assoufi B, Huston D, Dickason R, Jeannin P, Kay AB, Corrigan C. Secretion of the eosinophil-active cytokines interleukin-5, granulocyte/macrophage colony-stimulating factor and interleukin-3 by bronchoalveolar lavage CD4+ and CD8+ T cell lines in atopic asthmatics, and atopic and non-atopic controls. Eur J Immunol. 1995 Oct;25(10):2727–2731. [PubMed]
  • Marsh DG, Neely JD, Breazeale DR, Ghosh B, Freidhoff LR, Ehrlich-Kautzky E, Schou C, Krishnaswamy G, Beaty TH. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science. 1994 May 20;264(5162):1152–1156. [PubMed]
  • Massey W, Friedman B, Kato M, Cooper P, Kagey-Sobotka A, Lichtenstein LM, Schleimer RP. Appearance of granulocyte-macrophage colony-stimulating factor activity at allergen-challenged cutaneous late-phase reaction sites. J Immunol. 1993 Feb 1;150(3):1084–1092. [PubMed]
  • Durham SR, Ying S, Varney VA, Jacobson MR, Sudderick RM, Mackay IS, Kay AB, Hamid QA. Cytokine messenger RNA expression for IL-3, IL-4, IL-5, and granulocyte/macrophage-colony-stimulating factor in the nasal mucosa after local allergen provocation: relationship to tissue eosinophilia. J Immunol. 1992 Apr 15;148(8):2390–2394. [PubMed]
  • Bentley AM, Meng Q, Robinson DS, Hamid Q, Kay AB, Durham SR. Increases in activated T lymphocytes, eosinophils, and cytokine mRNA expression for interleukin-5 and granulocyte/macrophage colony-stimulating factor in bronchial biopsies after allergen inhalation challenge in atopic asthmatics. Am J Respir Cell Mol Biol. 1993 Jan;8(1):35–42. [PubMed]
  • Chodakewitz JA, Kupper TS, Coleman DL. Keratinocyte-derived granulocyte/macrophage colony-stimulating factor induces DNA synthesis by peritoneal macrophages. J Immunol. 1988 Feb 1;140(3):832–836. [PubMed]
  • Szabolcs P, Avigan D, Gezelter S, Ciocon DH, Moore MA, Steinman RM, Young JW. Dendritic cells and macrophages can mature independently from a human bone marrow-derived, post-colony-forming unit intermediate. Blood. 1996 Jun 1;87(11):4520–4530. [PubMed]
  • Vremec D, Lieschke GJ, Dunn AR, Robb L, Metcalf D, Shortman K. The influence of granulocyte/macrophage colony-stimulating factor on dendritic cell levels in mouse lymphoid organs. Eur J Immunol. 1997 Jan;27(1):40–44. [PubMed]
  • Murphy WJ, Kumar V, Bennett M. Acute rejection of murine bone marrow allografts by natural killer cells and T cells. Differences in kinetics and target antigens recognized. J Exp Med. 1987 Nov 1;166(5):1499–1509. [PMC free article] [PubMed]
  • Heufler C, Koch F, Schuler G. Granulocyte/macrophage colony-stimulating factor and interleukin 1 mediate the maturation of murine epidermal Langerhans cells into potent immunostimulatory dendritic cells. J Exp Med. 1988 Feb 1;167(2):700–705. [PMC free article] [PubMed]
  • Rupec R, Magerstaedt R, Schirren CG, Sander E, Bieber T. Granulocyte/macrophage-colony-stimulating factor induces the migration of human epidermal Langerhans cells in vitro. Exp Dermatol. 1996 Apr;5(2):115–119. [PubMed]
  • O'Sullivan GM, Sluyter R, Boswell CM, Barnetson RS, Halliday GM. Modulation of Ia+ Langerhans cell numbers in vivo by cultured epidermis derived supernatants and by GM-CSF. Exp Dermatol. 1996 Feb;5(1):28–37. [PubMed]
  • Kaplan G, Walsh G, Guido LS, Meyn P, Burkhardt RA, Abalos RM, Barker J, Frindt PA, Fajardo TT, Celona R, et al. Novel responses of human skin to intradermal recombinant granulocyte/macrophage-colony-stimulating factor: Langerhans cell recruitment, keratinocyte growth, and enhanced wound healing. J Exp Med. 1992 Jun 1;175(6):1717–1728. [PMC free article] [PubMed]
  • Tazi A, Bouchonnet F, Grandsaigne M, Boumsell L, Hance AJ, Soler P. Evidence that granulocyte macrophage-colony-stimulating factor regulates the distribution and differentiated state of dendritic cells/Langerhans cells in human lung and lung cancers. J Clin Invest. 1993 Feb;91(2):566–576. [PMC free article] [PubMed]
  • Horsmanheimo L, Harvima IT, Järvikallio A, Harvima RJ, Naukkarinen A, Horsmanheimo M. Mast cells are one major source of interleukin-4 in atopic dermatitis. Br J Dermatol. 1994 Sep;131(3):348–353. [PubMed]
  • Braunstein S, Kaplan G, Gottlieb AB, Schwartz M, Walsh G, Abalos RM, Fajardo TT, Guido LS, Krueger JG. GM-CSF activates regenerative epidermal growth and stimulates keratinocyte proliferation in human skin in vivo. J Invest Dermatol. 1994 Oct;103(4):601–604. [PubMed]
  • Hancock GE, Kaplan G, Cohn ZA. Keratinocyte growth regulation by the products of immune cells. J Exp Med. 1988 Oct 1;168(4):1395–1402. [PMC free article] [PubMed]
  • Marini M, Vittori E, Hollemborg J, Mattoli S. Expression of the potent inflammatory cytokines, granulocyte-macrophage-colony-stimulating factor and interleukin-6 and interleukin-8, in bronchial epithelial cells of patients with asthma. J Allergy Clin Immunol. 1992 May;89(5):1001–1009. [PubMed]
  • Davies RJ, Wang JH, Trigg CJ, Devalia JL. Expression of granulocyte/macrophage-colony-stimulating factor, interleukin-8 and RANTES in the bronchial epithelium of mild asthmatics is down-regulated by inhaled beclomethasone dipropionate. Int Arch Allergy Immunol. 1995 May-Jun;107(1-3):428–429. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...