Hypothemycin inhibits the proliferative response and modulates the production of cytokines during T cell activation

Hypothemycin, a resorcylic acid lactone antibiotic, was identified as active in a screen for inhibitors of T cell activation. It was found to inhibit the proliferation of mouse and human T cells stimulated with anti-CD3 mAb+PMA and of human PBMC stimulated with anti-CD3 mAb alone. This inhibition wa...

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Bibliographic Details
Published in:Immunopharmacology 1999-11, Vol.44 (3), p.255-265
Main Authors: Camacho, Ramon, Staruch, Mary Jo, DaSilva, Carolyn, Koprak, Sam, Sewell, Tonya, Salituro, Gino, Dumont, Francis J
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cytokine regulation
Cytokines - drug effects
Cytokines - metabolism
Estrogens, Non-Steroidal - pharmacology
Humans
Hypothemycin
IL-2 production
Immunomodulators
Immunosuppressant
Immunosuppressive Agents - pharmacology
Lymphocyte Activation - drug effects
Medical sciences
Mice
Pharmacology. Drug treatments
RNA, Messenger - drug effects
RNA, Messenger - metabolism
T cell activation
T-Lymphocytes - drug effects
T-Lymphocytes - metabolism
Tacrolimus - pharmacology
Zearalenone - pharmacology
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Summary:Hypothemycin, a resorcylic acid lactone antibiotic, was identified as active in a screen for inhibitors of T cell activation. It was found to inhibit the proliferation of mouse and human T cells stimulated with anti-CD3 mAb+PMA and of human PBMC stimulated with anti-CD3 mAb alone. This inhibition was partially reversed by exogenous IL-2 indicating that it is not due to non-specific toxicity. Hypothemycin potently suppressed the production of IL-2 (IC50: 9 nM) but affected IL-2-induced proliferation to a lesser extent (IC50: 194 nM). Hypothemycin also inhibited IL-6, IL-10, IFN-γ and TNF-α production. By contrast, it markedly enhanced the production of IL-4, IL-5 and IL-13. These effects were seen both at the mRNA and protein secretion levels. Analysis of the effect of hypothemycin on CD69 induction suggested that it disrupts calcineurin-independent rather than calcineurin-dependent signaling. Furthermore, hypothemycin was able to inhibit the phosphorylation of ERK1/2 induced by PMA treatment of T cells. Therefore, hypothemycin represents an inhibitor of T cell activation with a novel mode of action and unique modulatory activity on cytokine production.
ISSN:0162-3109
DOI:10.1016/S0162-3109(99)00085-5