The Journal of Cell Biology, Vol 102, 145-150, Copyright © 1986 by The Rockefeller University Press
Cyclosporine A, an in vitro calmodulin antagonist, induces nuclear lobulations in human T cell lymphocytes and monocytes
JW Simons, SJ Noga, PM Colombani, WE Beschorner, DS Coffey and AD Hess
Cyclosporine A is a noncytotoxic, natural, 11 amino acid cyclic peptide
used clinically as an immunosuppressant to prevent organ rejection after
transplantation. Cyclosporine A is an in vitro calmodulin antagonist. At
the low concentrations required to inhibit calmodulin- dependent
phosphodiesterase in vitro, cyclosporine A causes a dramatic alteration in
the nuclear morphology of 23% of human peripheral blood mononuclear
leukocytes in vitro without loss of viability. The shape of the nucleus
changes from ovoid to a distinctive, radially splayed lobulated structure.
The changes occur in a dose-dependent manner in 60 min at 37 degrees C.
Specific monoclonal antibodies to human leukocytes identify the cells
susceptible to nuclear lobulation by cyclosporine A as OKT4
antigen-positive T cell lymphocytes and monocytes. The lobulated nuclei are
2N as determined by flow cytometric measurement of ethidium bromide
fluorescence of DNA. The cyclosporine A-induced lobulation of T cell nuclei
requires both physiologic temperature and metabolic energy. Although
structurally different than cyclosporine A, the calmodulin antagonists
R24571 and W-7 [N-(6-aminohexyl)-5-chloro-1- naphthalene-sulfonamide] also
produce T cell nuclear lobulations that are indistinguishable from the
nuclear lobulations caused by cyclosporine A. These data indicate that
nonmitotic structural elements that govern normal nuclear morphology in a
subset of mononuclear leukocytes appear to require a calmodulin-mediated
process. Cyclosporine A may be a useful noncytotoxic inhibitor of
calmodulin- dependent systems that influence nuclear structure and
function.
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