Anti-mycotics suppress interleukin-4 and interleukin-5 production in anti-CD3 plus anti-CD28-stimulated T cells from patients with atopic dermatitis.
It is reported that anti-mycotic agents are effective for the treatment of patients with atopic dermatitis. We studied the in vitro effects of anti-mycotics on T helper-1 and T helper-2 cytokine production in anti-CD3 plus anti-CD28-stimulated T cells from atopic dermatitis patients and normal donors. The amounts of interleukin-4 and interleukin-5 secreted by anti-CD3/CD28-stimulated T cells were higher in atopic dermatitis patients than in normal donors. Azole derivatives, ketoconazole, itraconazole, miconazole, and nonazole terbinafine hydrochloride, and tolnaftate reduced interleukin-4 and interleukin-5 secretion without altering that of interferon-gamma and interleukin-2 in anti-CD3/CD28-stimulated T cells from both atopic dermatitis patients and normal donors. The azole derivatives were more inhibitory than nonazole anti-mycotics. These anti-mycotics reduced the anti-CD3/CD28-induced mRNA expression and promoter activities for interleukin-4 and interleukin-5. The 3',5'-cyclic adenosine monophosphate analog dibutyryl 3',5'-cyclic adenosine monophosphate reversed the inhibitory effects of the anti-mycotics on interleukin-4 and interleukin-5 secretion, mRNA expression, and promoter activities. Anti-CD3/CD28 transiently (< or = 5 min) increased intracellular 3',5'-cyclic adenosine monophosphate in T cells, and the increase was greater in atopic dermatitis patients than in normal donors. The increase of 3',5'-cyclic adenosine monophosphate by anti-CD3/CD28 correlated with interleukin-4 and interleukin-5 secretion by anti-CD3/CD28. The transient 3',5'-cyclic adenosine monophosphate increase was suppressed by anti-mycotics, and azole derivatives were more suppressive than nonazoles. Azole derivatives inhibited the activity of cyclic adenosine monophosphate-synthesizing adenylate cyclase whereas terbinafine hydrochloride and tolnaftate enhanced the activity of 3',5'-cyclic adenosine monophosphate-hydrolyzing cyclic nucleotide phosphodiesterase in atopic dermatitis and normal T cells. These results suggest that the anti-mycotics may suppress interleukin-4 and interleukin-5 production by reducing 3',5'-cyclic adenosine monophosphate signal, and stress their potential use for the suppression of T helper-2-mediated allergic reactions.
Kanda
N
N
Department of Dermatology, Teikyo University, School of Medicine, Japan. nmk@med.teikyo-u.ac.jp
Enomoto
U
U
Watanabe
S
S
D000262:Adenylyl Cyclases / Q000378:metabolism; D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics* / Q000378:metabolism; D015848:Interleukin-5 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology
D000911:Antibodies, Monoclonal; D000935:Antifungal Agents; D018106:CD28 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D015848:Interleukin-5; D012333:RNA, Messenger; D015847:Interleukin-4; D007371:Interferon-gamma; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases