Differential control of TH1 versus TH2 cell responses by the combination of low-dose steroids with beta2-adrenergic agonists

Abstract

Background: Combination treatment with steroids and long-acting beta2-agonists provides greater asthma control than simply increasing the dose of steroids.

Objective: Although the effects of combination treatment with steroids and long-acting beta2-agonists have been attributed to their anti-inflammatory and bronchodilator effects, the ability of this combination to act synergistically on T cells has not been explored.

Methods: PBMCs from control subjects and allergic asthmatic patients were stimulated with PHA in the presence of low doses of fluticasone propionate (FP) with or without salmeterol for 72 hours. The inhibition of T-cell proliferation, cytokine production, and glucocorticoid receptor translocation was measured.

Results: Both groups showed a similar degree of inhibition of PHA-induced T-cell proliferation with FP (inhibitory concentration of 50% approximately 10(-9) mol/L) alone. Use of lower concentrations of FP (10(-12) to 10(-11) mol/L) in combination with salmeterol (10(-10) to 10(-7) mol/L) in control subjects provided similar inhibition of proliferation. This combination treatment was associated with significantly greater glucocorticoid receptor translocation into the cell nucleus compared with that seen with FP alone (10(-12) mol/L; P <.01). In contrast, FP-salmeterol failed to act synergistically in asthmatic patients. The 2-drug combination significantly inhibited production of TNF-alpha and IFN-gamma in both groups (P <.05) but failed to inhibit TH2 cytokine (IL-5 and IL-13) production by PBMCs from asthmatic patients. Because allergic inflammation is associated with increased levels of cellular phosphodiesterases that might degrade salmeterol-induced cyclic adenosine monophosphate, rolipram (10(-6) mol/L), a phosphodiesterase 4 inhibitor, was added to the FP-salmeterol combination. This triple combination of drugs enhanced inhibitory activity of low-dose steroids on T-cell proliferation in asthmatic patients and inhibited IL-13 production.

Conclusion: These data suggest that beta2-agonists in combination with low doses of steroids can suppress T-cell proliferation and TH1 cytokine production from healthy individuals, but suppression of T cells with a combination of FP and salmeterol in asthmatic patients requires inhibition of phosphodiesterases.