HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Höhler, T. Articles by Neurath, M. F. Search for Related Content PubMed PubMed Citation Articles by Höhler, T. Articles by Neurath, M. F. Pubmed/NCBI databases Gene GEO Profiles HomoloGene OMIM UniGene Compound via MeSH Substance via MeSH

A Genetic Basis for IFN- Production and T-bet Expression in Humans¹

Thomas Höhler^2,*, Esther Reuss^*, Petra Adams^*, Brigitte Bartsch^*, Benno Weigmann^*, Markus Wörns^*, Peter R. Galle^*, Anja Victor and Markus F. Neurath^*

^* Department of Internal Medicine and Institute for Medical Biometry, Epidemiology, and Informatics, Johannes Gutenberg-University, Mainz, Germany

Th1 and Th2 cytokines secreted by polarized effector T cells play a pivotal role in the development of autoimmune and allergic diseases. However, the genetic basis of cytokine production by T lymphocytes in humans is poorly understood. In this study, we investigated the genetic contribution to cytokine production and regulation of T cell-specific transcription factors in a prospective twin study. We found a substantial genetic contribution to the production of Th1 cytokines such as IFN- and TNF- with heritabilities of 0.85 (95% confidence intervals, 0.74–0.95) and 0.72 (0.50–0.93), respectively, whereas no genetic influence on production of the Th2 signature cytokine IL-4 was observed. Furthermore, the intrapair variability in IFN- production by isolated T cells was lower in monozygotic than in dizygotic twins. In contrast to GATA-3, NFAT, and NF-B, intrapair variability of T-bet, the master transcription factor of Th1 cells, was very low among monozygotic and high among dizygotic twins, indicative of a strong genetic influence on T-bet (heritability 0.93, 95% confidence interval, 0.84–1.0). Our data provide novel insights into the genetic regulation of human Th cell polarization. These data suggest that signature cytokines and cytokine signaling events of Th1 rather than Th2 cells are genetically determined and implicate that Th2-associated diseases in humans might be due to genetic variations in Th1 cytokine regulation via T-bet. This concept is highlighted by the recent finding that inactivation of the T-bet gene in mice results in development of clinical hallmark features of asthma.

This article has been cited by other articles:

				W. Cozen, P. S. Gill, M. T. Salam, A. Nieters, R. Masood, M. G. Cockburn, W. J. Gauderman, O. Martinez-Maza, B. N. Nathwani, M. C. Pike, et al. Interleukin-2, interleukin-12, and interferon-{gamma} levels and risk of young adult Hodgkin lymphoma Blood, April 1, 2008; 111(7): 3377 - 3382. [Abstract] [Full Text] [PDF]

				M. Schedel, L. A. Pinto, B. Schaub, P. Rosenstiel, D. Cherkasov, L. Cameron, N. Klopp, T. Illig, C. Vogelberg, S. K. Weiland, et al. IRF-1 Gene Variations Influence IgE Regulation and Atopy Am. J. Respir. Crit. Care Med., March 15, 2008; 177(6): 613 - 621. [Abstract] [Full Text] [PDF]

				U. De Fanis, F. Mori, R. J. Kurnat, W. K. Lee, M. Bova, N. F. Adkinson, and V. Casolaro GATA3 up-regulation associated with surface expression of CD294/CRTH2: a unique feature of human Th cells Blood, May 15, 2007; 109(10): 4343 - 4350. [Abstract] [Full Text] [PDF]

				M. Bachmann, C. Dragoi, M. A. Poleganov, J. Pfeilschifter, and H. Muhl Interleukin-18 directly activates T-bet expression and function via p38 mitogen-activated protein kinase and nuclear factor-{kappa}B in acute myeloid leukemia-derived predendritic KG-1 cells Mol. Cancer Ther., February 1, 2007; 6(2): 723 - 731. [Abstract] [Full Text] [PDF]