BACKGROUND: The immunosuppressive effects of tacrolimus are mediated by inhibition of cytokine production by inflammatory cells. The role of tacrolimus on cytokine production and release of chemical mediators in asthma is not known at present. OBJECTIVES: We compared the effects of tacrolimus on interleukin (IL)-5 and tumor necrosis factor-alpha (TNF-alpha) production and chemical mediator release from excised human lung tissue with those of steroids. METHODS: Human lung tissue was passively sensitized with serum from atopic patients then preincubated with tacrolimus (10(-6), 10(-7), 10(-8) M) or dexamethasone (10(-6) M) for 2 hours. The lung tissue was then exposed to 1.5 microg/mL of mite antigen and then cultured for 48 hours. Culture supernatants were collected and IL-5 and TNF-alpha levels were measured by ELISA. IL-5 and TNF-alpha messenger ribonucleic acid (mRNA) expression was also investigated by reverse transcriptase-polymerase chain reaction. The level of histamine and leukotriene E4 was also measured in the culture supernatant. In addition, tryptase staining was performed to compare degranulation of mast cells. RESULTS: Antigen stimulation increased histamine and leukotriene release in the supernatant. Tacrolimus significantly and dose-dependently inhibited the release of histamine and leukotriene; dexamethasone did not. The results of tryptase staining demonstrated that tacrolimus dose-dependently inhibited degranulation of mast cells, whereas dexamethasone did not. Antigen stimulation increased TNF-alpha and IL-5 protein production and mRNA expression. Tacrolimus and dexamethasone significantly inhibited TNF-alpha and IL-5 protein production and mRNA expression. CONCLUSIONS: Our results indicated that tacrolimus is more powerful in inhibition of cytokine production and release of chemical mediators than steroids, and suggested that this immunosuppressor drug might be useful for the treatment of asthma.
BACKGROUND: The immunosuppressive effects of tacrolimus are mediated by inhibition of cytokine production by inflammatory cells. The role of tacrolimus on cytokine production and release of chemical mediators in asthma is not known at present. OBJECTIVES: We compared the effects of tacrolimus on interleukin (IL)-5 and tumor necrosis factor-alpha (TNF-alpha) production and chemical mediator release from excised human lung tissue with those of steroids. METHODS:Human lung tissue was passively sensitized with serum from atopic patients then preincubated with tacrolimus (10(-6), 10(-7), 10(-8) M) or dexamethasone (10(-6) M) for 2 hours. The lung tissue was then exposed to 1.5 microg/mL of mite antigen and then cultured for 48 hours. Culture supernatants were collected and IL-5 and TNF-alpha levels were measured by ELISA. IL-5 and TNF-alpha messenger ribonucleic acid (mRNA) expression was also investigated by reverse transcriptase-polymerase chain reaction. The level of histamine and leukotriene E4 was also measured in the culture supernatant. In addition, tryptase staining was performed to compare degranulation of mast cells. RESULTS: Antigen stimulation increased histamine and leukotriene release in the supernatant. Tacrolimus significantly and dose-dependently inhibited the release of histamine and leukotriene; dexamethasone did not. The results of tryptase staining demonstrated that tacrolimus dose-dependently inhibited degranulation of mast cells, whereas dexamethasone did not. Antigen stimulation increased TNF-alpha and IL-5 protein production and mRNA expression. Tacrolimus and dexamethasone significantly inhibited TNF-alpha and IL-5 protein production and mRNA expression. CONCLUSIONS: Our results indicated that tacrolimus is more powerful in inhibition of cytokine production and release of chemical mediators than steroids, and suggested that this immunosuppressor drug might be useful for the treatment of asthma.