Background: STAT6 is an important transcription factor in interleukin-4 (IL-4) signaling, a key cytokine in atopic diseases and allergic asthma. STAT6 gene-targeted mice are unable to develop IgE and T helper 2 cell (Th2) responses in several models of allergic and infectious diseases. In experiments to further elucidate STAT6 functions in vivo, we unexpectedly observed severely impaired IL-4 functions in STAT6 heterozygous (STAT6+/–) mice which were further analyzed in this study. Methods: BALB/c mice, either wild-type (STAT6+/+), STAT6 heterozygous (STAT6+/–) or STAT6 deficient (STAT6–/–), were analyzed for their ability to mount an IL-4-induced IgE response in vitro and in vivo. Supernatants of stimulated B cells and sera of Leishmania major-infected mice were analyzed for IgE, IgG1 and IgG2a concentrations by ELISA. Transcripts accompanying IgE class switching were amplified by RT-PCR and the expression of CD23 and MHC class II molecules on B cells was assessed by FACS analysis. Results: B cells from STAT6+/– mice were unable to secrete IgE in vitro and in vivo and transcripts accompanying IgE class switching were drastically reduced, whereas IL-4-induced upregulation of MHC class II was unimpaired and CD23 expression levels were only slightly affected. Additionally, STAT6+/– mice were equally resistant to infection with L. major as STAT6-deficient (STAT6–/–) mice, due to a defect in mounting a Th2-dominated immune response. Conclusion: Different STAT6-dependent IL-4 functions require different thresholds of activated STAT6 molecules.

1.
Nelms K, Keegan AD, ZamoranoJ, Ryan JJ, Paul WE: The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol 1999;17:701–738.
2.
Kaplan MH, Schindler U, Smiley ST, Grusby MJ: Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 1996;4:313–319.
3.
Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S, Nakanishi K, Yoshida N, Kishimoto T, Akira S: Essential role of Stat6 in IL-4 signalling. Nature 1996;380:627–630.
4.
Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carlson RT, Tripp RA, Chu C, Quelle FW, Nosaka T, Vignali DA, Doherty PC, Grosveld G, Paul WE, Ihle JN: Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 1996;380:630–633.
5.
Akimoto T, Numata F, Tamura M, Takata Y, Higashida N, Takashi T, Takeda K, Akira S: Abrogation of bronchial eosinophilic inflammation and airway hyperreactivity in signal transducers and activators of transcription (STAT)6-deficient mice. J Exp Med 1998;187:1537–1542.
6.
Kuperman D, Schofield B, Wills-Karp M, Grusby MJ: Signal transducer and activator of transcription factor 6 (Stat6)-deficient mice are protected from antigen-induced airway hyperresponsiveness and mucus production. J Exp Med 1998;187:939–948.
7.
Stavnezer-Nordgren J, Sirlin S: Specificity of immunoglobulin heavy chain switch correlates with activity of germline heavy chain genes prior to switching. EMBO J 1986;5:95–102.
8.
Li SC, Rothman PB, Zhang J, Chan C, Hirsh D, Alt FW: Expression of I mu-C gamma hybrid germline transcripts subsequent to immunoglobulin heavy chain class switching. Int Immunol 1994;6:491–497.
9.
Linehan LA, Warren WD, Thompson PA, Grusby MJ, Berton MT: STAT6 is required for IL-4-induced germline Ig gene transcription and switch recombination. J Immunol 1998;161:302–310.
10.
Sadick MD, Heinzel FP, Holaday BJ, Pu RT, Dawkins RS, Locksley RM: Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism. J Exp Med 1990;171:115–127.
11.
Sacks D, Noben-Trauth N: The immunology of susceptibility and resistance to Leishmania major in mice. Nat Rev Immunol 2002;2:845–858.
12.
Patel BK, Pierce JH, LaRochelle WJ: Regulation of interleukin 4-mediated signaling by naturally occurring dominant negative and attenuated forms of human Stat6. Proc Natl Acad Sci USA 1998;95:172–177.
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.