Professional antigen-presenting cells (APC) such as monocytes and dendritic cells (DC) bearing high-affinity IgE receptors (FcΕRI) efficiently present IgE-bound antigens to T cells. FcΕRI expression is upregulated on APC from atopic donors, especially in inflamed tissues. These data suggest a pathophysiological concept of an IgE-mediated delayed-type hypersensitivity reaction in atopic diseases. However, FcΕRI ligation also leads to the synthesis of proinflammatory cytokines and other molecules involved in inflammatory reactions. The investigation of transcription factors mediating these effects has only recently commenced. In general, members of the NF-ĸB family are known to regulate APC function and differentiation, with the RelB subunit being especially important in DC generation. In addition, Ikaros and PU.1 have also been shown to be essential factors for DC differentiation, whereas Oct-2 is upregulated by differentiation towards macrophages. Recently, FcΕRI has been demonstrated to induce NF-ĸB activation via IĸB-α serine phosphorylation and degradation in monocytes and DC. Inhibitors of NF-ĸB activation such as N-acetylcysteine or N-tosyl-L-phenylalanine chloromethyl ketone can suppress FcΕRI-induced TNF-α and MCP-1 release. Interestingly, in human epidermal Langerhans’ cells (LC), NF-ĸB activation can only be observed when large amounts of FcΕRI are present. In addition, the composition of NF-ĸB complexes differs between monocytes, monocyte-derived DC and LC, suggesting a cell type-specific regulation. Moreover, the transcription factor NFAT is induced upon FcΕRI ligation in human APC. The elucidation of further transcription factors involved in FcΕRI signaling in APC should contribute to the employment of new inhibition strategies for the treatment of atopic and other inflammatory diseases.

Keywords:
IgE receptor, Antigen-presenting cells, NFAT, NF-ĸB, Transcription
1.
Kinet JP: The high-affinity IgE receptor (Fc epsilon RI): From physiology to pathology. Annu Rev Immunol 1999;17:931–972.
2.
Turner H, Kinet JP: Signalling through the high-affinity IgE receptor Fc epsilonRI. Nature 1999;402:B24–B30.
3.
Bieber T, de la Salle H, Wollenberg A, Hakimi J, Chizzonite R, Ring J, Hanau D, de la Salle C: Human epidermal Langerhans cells express the high affinity receptor for immunoglobulin E (Fc epsilon RI). J Exp Med 1992;175:1285–1290.
4.
Wang B, Rieger A, Kilgus O, Ochiai K, Maurer D, Fodinger D, Kinet JP, Stingl G: Epidermal Langerhans cells from normal human skin bind monomeric IgE via Fc epsilon RI. J Exp Med 1992;175:1353–1365.
5.
Maurer D, Fiebiger E, Ebner C, Reininger B, Fischer GF, Wichlas S, Jouvin MH, Schmitt-Egenolf M, Kraft D, Kinet JP, Stingl G: Peripheral blood dendritic cells express Fc epsilon RI as a complex composed of Fc epsilon RI alpha- and Fc epsilon RI gamma-chains and can use this receptor for IgE-mediated allergen presentation. J Immunol 1996;157:607–616.
6.
Maurer D, Fiebiger E, Reininger B, Wolff- Winiski B, Jouvin MH, Kilgus O, Kinet JP, Stingl G: Expression of functional high affinity immunoglobulin E receptors (Fc epsilon RI) on monocytes of atopic individuals. J Exp Med 1994;179:745–750.
7.
Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature 1998;392:245–252.
8.
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;106:446–453.
9.
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;69:335–341.
10.
Maurer D, Ebner C, Reininger B, Fiebiger E, Kraft D, Kinet JP, Stingl G: The high affinity IgE receptor (Fc epsilon RI) mediates IgE-dependent allergen presentation. J Immunol 1995;154:6285–6290.
11.
Maurer D, Fiebiger E, Reininger B, Ebner C, Petzelbauer P, Shi GP, Chapman HA, Stingl G: Fc epsilon receptor I on dendritic cells delivers IgE-bound multivalent antigens into a cathepsin S-dependent pathway of MHC class II presentation. J Immunol 1998;161:2731–2739.
12.
Bieber T: Fc epsilon RI-expressing antigen-presenting cells: New players in the atopic game. Immunol Today 1997;18:311–313.
13.
Baeuerle PA, Henkel T: Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 1994;12:141–179.
14.
Ghosh S, May MJ, Kopp EB: NF-kappa B and Rel proteins: Evolutionarily conserved mediators of immune responses. Annu Rev Immunol 1998;16:225–260.
15.
Feuillard J, Korner M, Fourcade C, Costa A, Binet JL, Debre P, Raphael M: Visualization of the endogenous NF-kappa B p50 subunit in the nucleus of follicular dendritic cells in germinal centers. J Immunol 1994;152:12–21.
16.
Granelli-Piperno A, Pope M, Inaba K, Steinman RM: Coexpression of NF-kappa B/Rel and Sp1 transcription factors in human immunodeficiency virus 1-induced, dendritic cell-T-cell syncytia. Proc Natl Acad Sci USA 1995;92:10944–10948.
17.
Burkly L, Hession C, Ogata L, Reilly C, Marconi LA, Olson D, Tizard R, Cate R, Lo D: Expression of relB is required for the development of thymic medulla and dendritic cells. Nature 1995;373:531–536.
18.
Wu L, D’Amico A, Winkel KD, Suter M, Lo D, Shortman K: RelB is essential for the development of myeloid-related CD8alpha– dendritic cells but not of lymphoid-related CD8alpha+ dendritic cells. Immunity 1998;9:839–847.
19.
Pettit AR, Quinn C, MacDonald KP, Cavanagh LL, Thomas G, Townsend W, Handel M, Thomas R: Nuclear localization of RelB is associated with effective antigen-presenting cell function. J Immunol 1997;159:3681–3691.
20.
Neumann M, Fries H, Scheicher C, Keikavoussi P, Kolb-Maurer A, Brocker E, Serfling E, Kämpgen E: Differential expression of Rel/NF-kappaB and octamer factors is a hallmark of the generation and maturation of dendritic cells. Blood 2000;95:277–285.
21.
Rescigno M, Martino M, Sutherland CL, Gold MR, Ricciardi-Castagnoli P: Dendritic cell survival and maturation are regulated by different signaling pathways. J Exp Med 1998;188:2175–2180.
22.
Wu L, Nichogiannopoulou A, Shortman K, Georgopoulos K: Cell-autonomous defects in dendritic cell populations of Ikaros mutant mice point to a developmental relationship with the lymphoid lineage. Immunity 1997;7:483–492.
23.
Guerriero A, Langmuir PB, Spain LM, Scott EW: PU.1 is required for myeloid-derived but not lymphoid-derived dendritic cells. Blood 2000;95:879–885.
24.
Pelletier C, Varin-Blank N, Rivera J, Iannascoli B, Marchand F, David B, Weyer A, Blank U: Fc epsilonRI-mediated induction of TNF-alpha gene expression in the RBL-2H3 mast cell line: Regulation by a novel NF-kappaB-like nuclear binding complex. J Immunol 1998;161:4768–4776.
25.
Marquardt DL, Walker LL: Dependence of mast cell IgE-mediated cytokine production on nuclear factor-kappaB activity. J Allergy Clin Immunol 2000;105:500–505.
26.
Hutchinson LE, McCloskey MA: Fc epsilon RI-mediated induction of nuclear factor of activated T-cells. J Biol Chem 1995;270:16333–16338.
27.
Prieschl EE, Gouilleux-Gruart V, Walker C, Harrer NE, Baumruker T: A nuclear factor of activated T cell-like transcription factor in mast cells is involved in IL-5 gene regulation after IgE plus antigen stimulation. J Immunol 1995;154:6112–6119.
28.
Turner H, Cantrell DA: Distinct Ras effector pathways are involved in Fc epsilon R1 regulation of the transcriptional activity of Elk-1 and NFAT in mast cells. J Exp Med 1997;185:43–53.
29.
Turner H, Gomez M, McKenzie E, Kirchem A, Lennard A, Cantrell DA: Rac-1 regulates nuclear factor of activated T cells (NFAT) C1 nuclear translocation in response to Fcepsilon receptor type 1 stimulation of mast cells. J Exp Med 1998;188:527–537.
30.
Prieschl EE, Pendl GG, Elbe A, Serfling E, Harrer NE, Stingl G, Baumruker T: Induction of the TNF-alpha promoter in the murine dendritic cell line 18 and the murine mast cell line CPII is differently regulated. J Immunol 1996;157:2645–2653.
31.
Ten RM, McKinstry MJ, Bren GD, Paya CV: Signal transduction pathways triggered by the FcepsilonRIIb receptor (CD23) in human monocytes lead to nuclear factor-kappaB activation. J Allergy Clin Immunol 1999;104:376–387.
32.
Ten RM, McKinstry MJ, Trushin SA, Asin S, Paya CV: The signal transduction pathway of CD23 (Fc epsilon RIIb) targets I kappa B kinase. J Immunol 1999;163:3851–3857.
33.
Wollenberg A, Wen SP, Bieber T: Langerhans cell phenotyping: A new tool for differential diagnosis of inflammatory skin diseases. Lancet 1995;346:1626–1627.
34.
Mommaas AM, Mulder AA, Jordens R, Out C, Tan MC, Cresswell P, Kluin PM, Koning F: Human epidermal Langerhans cells lack functional mannose receptors and a fully developed endosomal/lysosomal compartment for loading of HLA class II molecules. Eur J Immunol 1999;29:571–580.
35.
Jürgens M, Wollenberg A, Hanau D, de la Salle H, Bieber T: Activation of human epidermal Langerhans cells by engagement of the high affinity receptor for IgE, Fc epsilon RI. J Immunol 1995;155:5184–5189.
36.
Hoey T, Sun YL, Williamson K, Xu X: Isolation of two new members of the NF-AT gene family and functional characterization of the NF-AT proteins. Immunity 1995;2:461–472.
37.
Masuda ES, Naito Y, Tokumitsu H, Campbell D, Saito F, Hannum C, Arai K, Arai N: NFATx, a novel member of the nuclear factor of activated T cells family that is expressed predominantly in the thymus. Mol Cell Biol 1995;15:2697–2706.
38.
Xia Y, McMillin JB, Lewis A, Moore M, Zhu WG, Williams RS, Kellems RE: Electrical stimulation of neonatal cardiac myocytes activates the NFAT3 and GATA4 pathways and up-regulates the adenylosuccinate synthetase 1 gene. J Biol Chem 2000;275:1855–1863.
39.
Katoh N, Kraft S, Wessendorf JH, Bieber T: The high-affinity IgE receptor (FcepsilonRI) blocks apoptosis in normal human monocytes. J Clin Invest 2000;105:183–190.
40.
Katoh N, Bieber T: FcεRI mediates production of proinflammatory cytokines by human monocytes and monocyte-derived dendritic cells (abstract). J Invest Dermatol 1998;110:647.
41.
Macian F, Garcia-Rodriguez C, Rao A: Gene expression elicited by NFAT in the presence or absence of cooperative recruitment of Fos and Jun. EMBO J 2000;19:4783–4795.
42.
Lapidus CS, Schwarz DF, Honig PJ: Atopic dermatitis in children: Who cares? Who pays? J Am Acad Dermatol 1993;28:699–703.
43.
Smith DH, Malone DC, Lawson KA, Okamoto LJ, Battista C, Saunders WB: A national estimate of the economic costs of asthma. Am J Respir Crit Care Med 1997;156:787–793.
44.
Ruzicka T, Bieber T, Schöpf E, Rubins A, Dobozy A, Bos JD, Jablonska S, Ahmed I, Thestrup-Pedersen K, Daniel F, Finzi A, Reitamo S: A short-term trial of tacrolimus ointment for atopic dermatitis. European Tacrolimus Multicenter Atopic Dermatitis Study Group. N Engl J Med 1997;337:816–821.
45.
Panhans-Gross A, Novak N, Kraft S, Bieber T: Human epidermal Langerhans’ cells are targets for the immunosuppressive macrolide tacrolimus (FK506). J Allergy Clin Immunol 2001;107:345–352.
46.
Fruman DA, Bierer BE, Benes JE, Burakoff SJ, Austen KF, Katz HR: The complex of FK506-binding protein 12 and FK506 inhibits calcineurin phosphatase activity and IgE activation-induced cytokine transcripts, but not exocytosis, in mouse mast cells. J Immunol 1995;154:1846–1851.
47.
Kaye RE, Fruman DA, Bierer BE, Albers MW, Zydowsky LD, Ho SI, Jin YJ, Castells MC, Schreiber SL, Walsh CT, et al: Effects of cyclosporin A and FK506 on Fc epsilon receptor type I-initiated increases in cytokine mRNA in mouse bone marrow-derived progenitor mast cells: Resistance to FK506 is associated with a deficiency in FK506-binding protein FKBP12. Proc Natl Acad Sci USA 1992;89:8542–8546.
48.
Okamoto S, Mukaida N, Yasumoto K, Rice N, Ishikawa Y, Horiguchi H, Murakami S, Matsushima K: The interleukin-8 AP-1 and kappa B-like sites are genetic end targets of FK506-sensitive pathway accompanied by calcium mobilization. J Biol Chem 1994;269:8582–8589.
49.
Mazzeo D, Panina-Bordignon P, Recalde H, Sinigaglia F, D’Ambrosio D: Decreased IL-12 production and Th1 cell development by acetyl salicylic acid-mediated inhibition of NF-kappaB. Eur J Immunol 1998;28:3205–3213.
50.
Verhasselt V, Vanden Berghe W, Vanderheyde N, Willems F, Haegeman G, Goldman M: N-acetyl-L-cysteine inhibits primary human T cell responses at the dendritic cell level: Association with NF-kappaB inhibition. J Immunol 1999;162:2569–2574.
51.
Lin YZ, Yao SY, Veach RA, Torgerson TR, Hawiger J: Inhibition of nuclear translocation of transcription factor NF-kappa B by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence. J Biol Chem 1995;270:14255–14258.
52.
Rissoan MC, Soumelis V, Kadowaki N, Grouard G, Briere F, de Waal Malefyt R, Liu YJ: Reciprocal control of T helper cell and dendritic cell differentiation. Science 1999;283:1183–1186.
53.
Langenkamp A, Messi M, Lanzavecchia A, Sallusto F: Kinetics of dendritic cell activation: Impact on priming of Th1, Th2 and nonpolarized T cells. Nat Immunol 2000;1:311–316.
54.
Rengarajan J, Szabo SJ, Glimcher LH: Transcriptional regulation of Th1/Th2 polarization. Immunol Today 2000;21:479–483.
55.
Kapsenberg ML, Hilkens CM, Wierenga EA, Kalinski P: The role of antigen-presenting cells in the regulation of allergen-specific T cell responses. Curr Opin Immunol 1998;10:607–613.
56.
Tanaka H, Demeure CE, Rubio M, Delespesse G, Sarfati M: Human monocyte-derived dendritic cells induce naive T cell differentiation into T helper cell type 2 (Th2) or Th1/Th2 effectors. Role of stimulator/responder ratio. J Exp Med 2000;192:405–412.
57.
Murphy TL, Cleveland MG, Kulesza P, Magram J, Murphy KM: Regulation of interleukin 12 p40 expression through an NF-kappa B half-site. Mol Cell Biol 1995;15:5258–5267.
58.
Zhang JS, Feng WG, Li CL, Wang XY, Chang ZL: NF-kappaB regulates the LPS-induced expression of interleukin 12 p40 in murine peritoneal macrophages: Roles of PKC, PKA, ERK, p38 MAPK, and proteasome. Cell Immunol 2000;204:38–45.
59.
Sanjabi S, Hoffmann A, Liou HC, Baltimore D, Smale ST: Selective requirement for c-Rel during IL-12 P40 gene induction in macrophages. Proc Natl Acad Sci USA 2000;97:12705–12710.
© 2001 S. Karger AG, Basel
2001
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.