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 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-gamma and TNF-alpha 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.
Camacho
R
R
Department of Immunology and Rheumatology, Merck Research Laboratories, Rahway, NJ 07065, USA.
Staruch
M J
MJ
DaSilva
C
C
Koprak
S
S
Sewell
T
T
Salituro
G
G
Dumont
F J
FJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D015025:Zearalenone / Q000494:pharmacology / Q000031:analogs & derivatives
D000970:Antineoplastic Agents; D016207:Cytokines; D004968:Estrogens, Non-Steroidal; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; C120440:hypothemycin; D015025:Zearalenone; D016559:Tacrolimus