RESUMO
The immunosuppressive macrolide rapamycin shows marked structural similarity to FK-506, and like FK-506 inhibits the activation of cultured T and B lymphocytes at concentrations as low as 10(-10) M. However, rapamycin blocks T-lymphocyte proliferation at a much later stage than FK-506. It also inhibits human, porcine and murine T- and B-lymphocyte activation by all pathways tested, including pathways which are insensitive to FK-506, such as interleukin-2 (IL-2)-mediated proliferation of IL-2-dependent T-cell lines, activation of human peripheral blood T lymphocytes by phorbol ester and anti-CD28 and activation of murine B lymphocytes by bacterial lipopolysaccharide. Thus these two macrolides that bind competitively to the same major intracellular receptor protein inhibit T- and B-lymphocyte activation by quite distinct mechanisms.
Assuntos
Antibacterianos/farmacologia , Linfócitos B/imunologia , Imunossupressores/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Polienos/farmacologia , Linfócitos T/imunologia , Animais , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Ciclosporinas/farmacologia , Interações Medicamentosas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos CBA , Mitógenos/imunologia , Sirolimo , Suínos , TacrolimoAssuntos
Antibacterianos/farmacologia , Imunossupressores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Animais , Calcimicina/farmacologia , Concanavalina A/farmacologia , Expressão Gênica/efeitos dos fármacos , Técnicas In Vitro , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/genética , Dibutirato de 12,13-Forbol/farmacologia , Suínos , Tacrolimo , Fatores de TempoAssuntos
Antibacterianos/farmacologia , Imunossupressores/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Isomerases de Aminoácido/antagonistas & inibidores , Animais , Cálcio/metabolismo , Canais de Cálcio/efeitos dos fármacos , Humanos , Técnicas In Vitro , Mitocôndrias Hepáticas/enzimologia , Mitocôndrias Hepáticas/metabolismo , Peptidilprolil Isomerase , Ratos , Suínos , TacrolimoRESUMO
The novel immunosuppressive drug FK-506 inhibits the induction of lymphocyte proliferation in vitro by mitogenic combinations of phorbol esters and calcium ionophores. Early events inducible by phorbol esters alone are unaffected, while changes induced by calcium ionophores alone are completely suppressed by as little as 0.1 nM FK-506. The event in lymphocyte activation inhibited by FK-506 is completed early in the response. Its completion requires the provision of a Ca2+ signal and concurrent activation of protein kinase C and is accelerated as a function of the strength of protein kinase C activation.
Assuntos
Antibacterianos/farmacologia , Imunossupressores/farmacologia , Animais , Calcimicina/farmacologia , Cálcio/fisiologia , Ciclosporinas/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Proteína Quinase C/fisiologia , Suínos , Tacrolimo , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
Nanamolar concentrations of the immunosuppressive drug FK-506 inhibit the induction of T-lymphocyte proliferation by the lectins concanavalin A (Con A) and phytohaemagglutinin (PHA). Activation by Con A is more sensitive to inhibition than the response to PHA. FK-506 inhibits an early Ca2+-dependent step in the activation process, and its effects are not reversible by the addition of recombinant interleukin-2 (IL-2) or lymphokine-rich culture supernatant. While the effects of suboptimal concentrations of FK-506 and cyclosporin A (CsA) are additive, FK-506 does not enhance the effects of optimal concentrations of CsA. Both drugs also have similar effects on the expression of specific mRNA in Con A-activated lymphocytes. A brief preincubation of unstimulated cells with FK-506 irreversibly inhibits their subsequent responsiveness to Con A. The mechanism of action of FK-506 thus resembles that of CsA, except that it is effective at two to three orders of magnitude lower concentrations and its effects are much less readily reversible.
