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International Immunology Advance Access originally published online on April 5, 2004
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International Immunology, Vol. 16, No. 5, pp. 643-653, May 2004
© 2004 Japanese Society for Immunology

Up-regulation of IL-4 production by the activated cAMP/cAMP-dependent protein kinase (protein kinase A) pathway in CD3/CD28-stimulated naive T cells

Koji Tokoyoda1, Kazutake Tsujikawa1, Hiroaki Matsushita1, Yuichi Ono1, Tamon Hayashi1, Yohsuke Harada2, Ryo Abe2, Masato Kubo2 and Hiroshi Yamamoto1

1 Department of Immunology, Graduate School of Pharmaceutical Sciences, Osaka University, 1–6 Yamadaoka, Suita, Osaka 565-0871, Japan 2 Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan

Correspondence to: K. Tsujikawa; E-mail: tujikawa{at}phs.osaka-u.ac.jp
Transmitting editor: T. Saito

The signal transduction of the cAMP/cAMP-dependent protein kinase [protein kinase A (PKA)] pathway through multiple receptors is critical for many processes in all cell types. In T cells, the engagement of both the TCR–CD3 complex and the CD28 co-stimulatory molecule also induces cAMP, and subsequently activates PKA. It is believed that elevation of cAMP levels in T cells is inhibitory of IL-2 production and T cell proliferation. However, the function and detailed signal transduction mechanisms of the cAMP/PKA pathway in naive Th cells are less well understood. In this study, we show that calcitonin gene-related peptide (CGRP) down-regulates IL-2 and IFN-{gamma} production and up-regulates IL-4 production to promote Th2 differentiation by moderate activation of the cAMP/PKA pathway via the CGRP receptor in the presence of a CD3/CD28 co-stimulation signal. The IL-4 production and transcriptional activation of Th2 cytokine mRNAs were also reproduced by the addition of a cAMP analogue, dibutyryl-cAMP, in CD3/CD28-stimulated naive Th cells. More interestingly, cAMP/PKA activation in naive Th cells stimulated with anti-CD3 plus anti-CD28 mAb is essential for inducing IL-4 production and promoting Th2 differentiation; in addition, NF-AT is a downstream effector of the cAMP/PKA signaling pathway. These findings indicate that the cAMP/PKA pathway transduces the critical activation signal to Th2 polarization by a CD3/CD28 co-stimulation signal and a PKA activating reagent.

Keywords: calcitonin gene-related peptide, NF-AT, Th1, Th2


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