Effects of cyclosporin A and dinactin on T-cell proliferation, interleukin-5 production, and murine pulmonary inflammation.
We compared the effects of cyclosporin A (CSA) and a macrotetrolide antibiotic, dinactin, on human T-cell proliferation and cytokine production induced by stimulation of the T-cell receptor alone (monoclonal antibody [mAb] directed against CD3) or in combination with costimulatory signals (mAbs directed against CD3 and CD28). These agents were also examined in a murine model of interleukin (IL)-5-mediated pulmonary inflammation. Dinactin inhibited T-cell proliferation induced by IL-2, by mAb to CD3, and by mAbs to CD3 plus alpha-CD28 with identical dose-response curves (IC50 = 10-20 ng/ml). Dinactin inhibited cytokine production with IC50 values of 10 ng/ml for IL-4 and IL-5 and 30 or 60 ng/ml for interferon-gamma or IL-2, respectively. Unlike CSA, exogenous IL-2 did not alter the dinactin-mediated effects on T cells, and nuclear run-on and steady-state messenger RNA (mRNA) analysis showed that dinactin inhibited cytokine production through a post-transcriptional mechanism. CSA selectively blocked T-cell receptor-induced T-cell proliferation and cytokine production (IC50 = 10 ng/ml). Under costimulatory conditions, IL-5 synthesis was only minimally inhibited by high concentrations of CSA, and at CSA concentrations of less than 125 ng/ml, IL-5 was significantly increased above control values. Dinactin and CSA reduced pulmonary eosinophilia when administered within 1 d of airway antigen challenge. Of the cytokine mRNAs examined in the lungs of CSA-pretreated, antigen-challenged mice, IL-5 mRNA levels were the least reduced, paralleling the resistance of IL-5 to CSA observed in vitro and suggesting a role for CD28 in the in vivo induction of IL-5.
Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
S P
SP
Umland
H
H
Shah
J P
JP
Jakway
J
J
Shortall
S
S
Razac
C G
CG
Garlisi
A
A
Falcone
T T
TT
Kung
D
D
Stelts
V
V
Hegde
M
M
Patel
M
M
Motasim Billah
R W
RW
Egan
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D015848:Interleukin-5 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D018942:Macrolides; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D012130:Respiratory Hypersensitivity / Q000276:immunology*
D000900:Anti-Bacterial Agents; D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D015848:Interleukin-5; D018942:Macrolides; D012333:RNA, Messenger; D016572:Cyclosporine; C016520:dinactin