Cholera toxin inhibits interleukin-2-induced, but enhances pertussis toxin-induced T-cell proliferation: regulation by cyclic nucleotides.
To understand the signals transmitted by interleukin-2 (IL-2) during T-cell proliferation, the effect of this cytokine was compared to the bacterial product pertussis toxin (PT). Both IL-2 and PT induced the incorporation of [3H]thymidine into T cells. Cholera toxin (CT) inhibited IL-2-induced, but enhanced PT-induced T-cell proliferation. The effect of CT is mimicked by the cyclic AMP (cAMP) analogue 2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (dicAMP) or by the phosphodiesterase inhibitors isobutylmethylxanthine and aminophylline. Measurement of the intracellular level of cAMP showed that CT enhanced this level during both IL-2 or PT incubation with T cells. To delineate the differential effects of cAMP on IL-2 versus PT activity, it was observed that the blocker of intracellular calcium (TMB8), or the guanosine triphosphate (GTP) analogue (GTP gamma S) inhibited both PT and IL-2 activities, whereas the protein kinase C (PKC) inhibitor (H7) was without effect for both stimuli. Further experiments showed that both IL-2 and PT stimulate the endogenous level of cGMP and that CT enhanced this level following PT activation, but reduced it following IL-2 activation of T cells. Hence, there is a major difference between IL-2 and PT activation of T cells in as far as their susceptibility to treatment with cholera toxin is concerned. Furthermore, an increase of cGMP level resulted in the enhancement of proliferation, whereas a decrease in cGMP level resulted in the inhibition of proliferation.
Maghazachi
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AA
Northeastern Ontario Regional Cancer Centre, Sudbury, Canada.
D000818:Animals; D002455:Cell Division / Q000276:immunology; D002772:Cholera Toxin / Q000276:immunology*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology*; D008297:Male; D037342:Pertussis Toxin; D051381:Rats; D011916:Rats, Inbred F344; D013601:T-Lymphocytes / Q000276:immunology*; D010566:Virulence Factors, Bordetella / Q000276:immunology*
D007376:Interleukin-2; D010566:Virulence Factors, Bordetella; D002772:Cholera Toxin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D006152:Cyclic GMP