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Antimicrobial Agents and Chemotherapy, November 1999, p. 2678-2684, Vol. 43, No. 11
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Erythromycin Inhibits Transcriptional Activation of NF-kappa B, but not NFAT, through Calcineurin-Independent Signaling in T Cells

Yosuke Aoki* and Peter N. Kao

Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, California 94305

Received 9 April 1999/Returned for modification 10 June 1999/Accepted 20 August 1999

The molecular mechanism of the anti-inflammatory effect of erythromycin (EM) was investigated at the level of transcriptional regulation of cytokine gene expression in T cells. EM (>10-6 M) significantly inhibited interleukin-8 (IL-8) expression but not IL-2 expression from T cells induced with 20 ng of phorbol 12-myristate 13-acetate (PMA) per ml plus 2 µM calcium ionophore (P-I). In electrophoretic mobility shift assays EM at 10-7 to 10-5 M concentrations inhibited nuclear factor kappa B (NF-kappa B) DNA-binding activities induced by P-I. Reporter gene assays also showed that EM (10-5 M) inhibited IL-8 NF-kappa B transcription by 37%. The inhibitory effects of EM on transcriptional activation of IL-2 and DNA-binding activity of nuclear factor of activated T cells (NFAT) were not seen in T cells. On the other hand, FK506, which is also a macrolide derivative, inhibited transcriptional activation of both NF-kappa B and NFAT more strongly than EM did. The mechanism of EM inhibition of transactivation of NF-kappa B was further investigated in transiently transfected T cells that express calcineurin A and B subunits. Expression of calcineurin did not render transactivation of NF-kappa B in T cells more resistant to EM, while the inhibitory effect of FK506 on transactivation of NF-kappa B was attenuated. These findings indicate that EM is capable of inhibiting expression of the IL-8 gene in T cells through transcriptional inhibition and that this inhibition is mediated through a non-calcineurin-dependent signaling event in T lymphocytes.

* Corresponding author. Present address: Pulmonary Division, Department of Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan. Phone: 81-952-34-2372. Fax: 81-952-34-2017. E-mail: aokiy3{at}smsnet.saga-med.ac.jp.

Antimicrobial Agents and Chemotherapy, November 1999, p. 2678-2684, Vol. 43, No. 11
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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