Tetranactin

Tetranactin, a hydrophobic cyclic antibiotic produced by Streptomyces aureus, has previously been shown to suppress in vitro activation of rat lymphocytes by concanavalin A as well as the onset of experimental autoimmune uveoretinitis in Lewis rats. Here we report the effects of tetranactin on human T and NK lymphocytes in vitro. Tetranactin, at concentrations up to 100 ng/ml, was not toxic to human lymphocytes but completely abrogated the proliferation of human T lymphocytes in response to allogeneic cells in mixed lymphocyte cultures. Tetranactin also blocked the initiation of proliferation in response to interleukin-2, but did not block proliferation of interleukin-2-activated cells. Tetranactin also blocked generation of cytotoxic T lymphocytes and activated killer cells in the mixed lymphocyte culture. However, up to 100 ng/ml tetranactin did not alter the lytic activity of cytotoxic T or NK lymphocytes generated in its absence. The ability of low doses of tetranactin to block the induction of lymphoproliferation is similar to the action of cyclosporin A. Since cyclosporin A is also a cyclic hydrophobic molecule, the immunosuppressive actions of these two agents may involve a similar mechanism.

The manner in which molecular structure of the carrier and the lipid composition of the membrane modulate the membrane selectivity among monovalent cations has been investigated for nonactin, trinactin, and tetranactin, which differ only in their degrees of methylation, and for membranes made of two lipids, phosphatidyl ethanolamine and glyceryl dioleate, in which "equilibrium" and "kinetic" aspects of permeation, respectively, are emphasized. Bilayer permeability ratios for Li, Na, K, Rb, Cs, Tl,and NH4 have been characterized and resolved into "equilibrium" and "kinetic" components using a model for carrier-mediated membrane transport which includes both a trapezoid energy barrier for translocation of the complex across the membrane interior and a potential-dependence of the loading and unloading of ions at the membrane-solution interfaces. The bilayer permeability properties due to tetranactin have been characterized in each of these lipids and found not only to be regular but to be systematically related to those of the less methylated homologues, trinactin and nonactin. This analysis has led to the following conclusions: (1) The change in lipid composition alters the relative contributions of "kinetic" vs. "equilibrium" components to the observed carrier-mediated selectivity. (2) Increased methylation of the carrier increases the contribution of the "kinetic" component to the selectivity relative to that of the "equilibrium" component and additionally alters the "equilibrium component sufficiently that an inversion of Cs--Na selectivity occurs between trinactin and tetranactin. (3) For all ions and carriers examined, the "reaction plane" for ion-carrier complexation and the width for the "diffusion barrier can be represented by the same two parameters, independent of the ion or carrier, so that in all cases the complexation reaction senses 10% of the applied potential and the plateau of the "diffusion barrier" extends across 70% of the membrane interior.

Macrotetrolide antibiotic polynactins [dinactin, trinactin and tetranactin (1:4:5)] are hydrophobic cyclic esters produced by Streptomyces aureus. Polynactins (PN) and their major component tetranactin (TN) delayed or suppressed the onset of S-antigen-induced experimental autoimmune uveoretinitis (EAU) in Lewis rats. Termination of treatment with PN or TN before day 14 of immunization resulted in a delayed onset of EAU in many animals. Thus, the immunosuppressive effect of PN and TN was not lasting. PN and TN suppressed anti-S-antigen antibody formation. Skin hypersensitivity tests indicated suppression by PN of the delayed-type rather than Arthus type hypersensitivity to S-antigen. PN, TN and trinactin all inhibited 3H-thymidine incorporation into concanavalin A-treated lymphocytes at the early stage of cell activation. For each drug, 50% inhibition was obtained at about 0.1 ng/ml. Under the incubation condition that the cells were exposed to TN for 21 hours, cell viability remained unchanged up to 100 ng/ml of TN. It is evident that PN and TN suppress T-lymphocyte proliferation without cell injury. These results suggest that PN and TN inhibit the onset of EAU primarily through the suppression of cell-mediated immunity but also by affecting humoral immunity.