Keratinocytes enriched for epidermal stem cells differ in their response to IFN-γ from other proliferative keratinocytes
Jana Zeitvogel,
Thomas Werfel,
Miriam Wittmann,
Jana Zeitvogel
Department of Dermatology, Hannover Medical School, Hannover, Germany
Search for more papers by this authorThomas Werfel
Department of Dermatology, Hannover Medical School, Hannover, Germany
Search for more papers by this authorMiriam Wittmann
Department of Dermatology, Hannover Medical School, Hannover, Germany
Search for more papers by this authorJana Zeitvogel,
Thomas Werfel,
Miriam Wittmann,
Jana Zeitvogel
Department of Dermatology, Hannover Medical School, Hannover, Germany
Search for more papers by this authorThomas Werfel
Department of Dermatology, Hannover Medical School, Hannover, Germany
Search for more papers by this authorMiriam Wittmann
Department of Dermatology, Hannover Medical School, Hannover, Germany
Search for more papers by this authorMiriam Wittmann, MD, Department of Dermatology, Hannover Medical School, Ricklinger Str. 5, D-30449 Hannover, Germany, Tel.: +49 511 9246 278, Fax: +49 511 9246 440, e-mail: [email protected]
Abstract
Abstract: The epidermis has a pool of adult stem cells [epidermal stem cells (ESC)]. Although the localization of ESC is well described, we lack a clear understanding of their role in perturbed conditions such as inflammation. One of the most important mediators in inflammatory skin diseases acting on keratinocytes (KCs) is interferon gamma (IFN-γ). The assumption that ESC might generate a protected niche prompted us to investigate their response to the pro-inflammatory cytokine IFN-γ. In this study, we isolated two populations of KCs according to their adherence ability. ESC enriched by adherence showed a higher CD29 and CD49f expression compared with other KCs. Surprisingly, surface expression of CD54 was more inducible upon IFN-γ stimulation in short-term cultures of the ESC subpopulation. In contrary to that, a markedly lower induction of IL-18 and reduced basal production of CCL2 were observable in ESC. No differences in IFN-γ-induced interleukin (IL)-10, CXCL10, CCL22 or transforming growth factor (TGF)β1 secretion were detectable between the two keratinocyte subpopulations. These results suggest that ESC respond to IFN-γ with a ‘restricted’ pattern of pro-inflammatory cytokines, and do not build up an anti-inflammatory microenvironment by means of TGF-β or IL-10. Activated ESC possess the capability to interact with infiltrating lymphocytes via CD54. In conclusion, the ESC compartment might actively contribute to the immunological properties of the skin organ.
References
- 1 Barrandon Y, Green H. Three clonal types of keratinocyte with different capacities for multiplication. Proc Natl Acad Sci U S A 1987: 84: 2302–2306.
- 2 Watt FM. Stem cell fate and patterning in mammalian epidermis. Curr Opin Genet Dev 2001: 11: 410–417.
- 3 Mackenzie IC, Bickenbach JR. Label-retaining keratinocytes and Langerhans cells in mouse epithelia. Cell Tissue Res 1985: 242: 551–556.
- 4 Lavker RM, Sun TT. Epidermal stem cells: properties, markers, and location. Proc Natl Acad Sci U S A 2000: 97: 13473–13475.
- 5 Potten CS, Bullock JC. Cell kinetic studies in the epidermis of the mouse. I. Changes in labeling index with time after tritiated thymidine administration. Experientia 1983: 39: 1125–1129.
- 6 Li A, Simmons PJ, Kaur P. Identification and isolation of candidate human keratinocyte stem cells based on cell surface phenotype. Proc Natl Acad Sci U S A 1998: 95: 3902–3907.
- 7 Watt FM, Celso CL, Silva-Vargas V. Epidermal stem cells: an update. Curr Opin Genet Dev 2006: 16: 518–524.
- 8 Jones PH, Watt FM. Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression. Cell 1993: 73: 713–724.
- 9 Jensen UB, Lowell S, Watt FM. The spatial relationship between stem cells and their progeny in the basal layer of human epidermis: a new view based on whole-mount labelling and lineage analysis. Development 1999: 126: 2409–2418.
- 10 Wan H, Stone MG, Simpson C et al. Desmosomal proteins, including desmoglein 3, serve as novel negative markers for epidermal stem cell-containing population of keratinocytes. J Cell Sci 2003: 116: 4239–4248.
- 11 Kim DS, Cho HJ, Choi HR, Kwon SB, Park KC. Isolation of human epidermal stem cells by adherence and the reconstruction of skin equivalents. Cell Mol Life Sci 2004: 61: 2774–2781.
- 12 Bata-Csorgo Z, Hammerberg C, Voorhees JJ, Cooper KD. Kinetics and regulation of human keratinocyte stem cell growth in short-term primary ex vivo culture. Cooperative growth factors from psoriatic lesional T lymphocytes stimulate proliferation among psoriatic uninvolved, but not normal, stem keratinocytes. J Clin Invest 1995: 95: 317–327.
- 13 Wittmann M, Purwar R, Hartmann C, Gutzmer R, Werfel T. Human keratinocytes respond to interleukin-18: implication for the course of chronic inflammatory skin diseases. J Invest Dermatol 2005: 124: 1225–1233.
- 14 Wittmann M, Alter M, Stunkel T, Kapp A, Werfel T. Cell-to-cell contact between activated CD4 + T lymphocytes and unprimed monocytes interferes with a TH1 response. J Allergy Clin Immunol 2004: 114: 965–973.
- 15 Lajtha LG. Stem cell concepts. Differentiation 1979: 14: 23–34.
- 16 Fuchs E, Segre JA. Stem cells: a new lease on life. Cell 2000: 100: 143–155.
- 17 Pouliot N, Redvers RP, Ellis S, Saunders NA, Kaur P. Optimization of a transplant model to assess skin reconstitution from stem cell-enriched primary human keratinocyte populations. Exp Dermatol 2005: 14: 60–69.
- 18 Terunuma A, Kapoor V, Yee C, Telford WG, Udey MC, Vogel JC. Stem cell activity of human side population and alpha6 integrin-bright keratinocytes defined by a quantitative in vivo assay. Stem Cells 2007: 25: 664–669.
- 19 Triel C, Vestergaard ME, Bolund L, Jensen TG, Jensen UB. Side population cells in human and mouse epidermis lack stem cell characteristics. Exp Cell Res 2004: 295: 79–90.
- 20 Nickoloff BJ, Griffiths CE, Barker JN. The role of adhesion molecules, chemotactic factors, and cytokines in inflammatory and neoplastic skin disease – 1990 update. J Invest Dermatol 1990: 94: 151S–157S.
- 21 Nickoloff BJ, Turka LA. Keratinocytes: key immunocytes of the integument. Am J Pathol 1993: 143: 325–331.
- 22 Garioch JJ, Mackie RM, Campbell I, Forsyth A. Keratinocyte expression of intercellular adhesion molecule 1 (ICAM-1) correlated with infiltration of lymphocyte function associated antigen 1 (LFA-1) positive cells in evolving allergic contact dermatitis reactions. Histopathology 1991: 19: 351–354.
- 23 Gottlieb S, Hayes E, Gilleaudeau P, Cardinale I, Gottlieb AB, Krueger JG. Cellular actions of etretinate in psoriasis: enhanced epidermal differentiation and reduced cell-mediated inflammation are unexpected outcomes. J Cutan Pathol 1996: 23: 404–418.
- 24 Griffiths CE, Nickoloff BJ. Keratinocyte intercellular adhesion molecule-1 (ICAM-1) expression precedes dermal T lymphocytic infiltration in allergic contact dermatitis (Rhus dermatitis). Am J Pathol 1989: 135: 1045–1053.
- 25 Okamoto S, Takahashi S, Inoue T et al. Cutaneous chronic graft-versus-host disease localized to the field of total lymphoid irradiation. Bone Marrow Transplant 1996: 17: 111–113.
- 26 Singer KH, Tuck DT, Sampson HA, Hall RP. Epidermal keratinocytes express the adhesion molecule intercellular adhesion molecule-1 in inflammatory dermatoses. J Invest Dermatol 1989: 92: 746–750.
- 27 Dustin ML, Singer KH, Tuck DT, Springer TA. Adhesion of T lymphoblasts to epidermal keratinocytes is regulated by interferon gamma and is mediated by intercellular adhesion molecule 1 (ICAM-1). J Exp Med 1988: 167: 1323–1340.
- 28 Griffiths CE, Voorhees JJ, Nickoloff BJ. Gamma interferon induces different keratinocyte cellular patterns of expression of HLA-DR and DQ and intercellular adhesion molecule-I (ICAM-I) antigens. Br J Dermatol 1989: 120: 1–8.
- 29 Barker JN, Mitra RS, Griffiths CE, Dixit VM, Nickoloff BJ. Keratinocytes as initiators of inflammation. Lancet 1991: 337: 211–214.
- 30 Sligh JE Jr, Ballantyne CM, Rich SS et al. Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1. Proc Natl Acad Sci U S A 1993: 90: 8529–8533.
- 31 Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994: 76: 301–314.
- 32 Dustin ML, Springer TA. T-cell receptor cross-linking transiently stimulates adhesiveness through LFA-1. Nature 1989: 341: 619–624.
- 33 Van Kooyk Y, Van De Wiel-van Kemenade P, Weder P, Kuijpers TW, Figdor CG. Enhancement of LFA-1-mediated cell adhesion by triggering through CD2 or CD3 on T lymphocytes. Nature 1989: 342: 811–813.
- 34 Gaglia JL, Greenfield EA, Mattoo A, Sharpe AH, Freeman GJ, Kuchroo VK. Intercellular adhesion molecule 1 is critical for activation of CD28-deficient T cells. J Immunol 2000: 165: 6091–6098.
- 35 Luksch CR, Winqvist O, Ozaki ME et al. Intercellular adhesion molecule-1 inhibits interleukin 4 production by naive T cells. Proc Natl Acad Sci U S A 1999: 96: 3023–3028.
- 36 Salomon B, Bluestone JA. LFA-1 interaction with ICAM-1 and ICAM-2 regulates Th2 cytokine production. J Immunol 1998: 161: 5138–5142.
- 37 Smits HH, De Jong EC, Schuitemaker JH et al. Intercellular adhesion molecule-1/LFA-1 ligation favors human Th1 development. J Immunol 2002: 168: 1710–1716.
- 38 Wittmann M, Werfel T. Interaction of keratinocytes with infiltrating lymphocytes in allergic eczematous skin diseases. Curr Opin Allergy Clin Immunol 2006: 6: 329–334.
- 39 Albanesi C, Scarponi C, Giustizieri ML, Girolomoni G. Keratinocytes in inflammatory skin diseases. Curr Drug Targets Inflamm Allergy 2005: 4: 329–334.
- 40 Barker JN, Sarma V, Mitra RS, Dixit VM, Nickoloff BJ. Marked synergism between tumor necrosis factor-alpha and interferon-gamma in regulation of keratinocyte-derived adhesion molecules and chemotactic factors. J Clin Invest 1990: 85: 605–608.
- 41 Gutzmer R, Langer K, Mommert S, Wittmann M, Kapp A, Werfel T. Human dendritic cells express the IL-18R and are chemoattracted to IL-18. J Immunol 2003: 171: 6363–6371.
Citing Literature
