Simvastatin requires activation in accessory cells to modulate T-cell responses in asthma and COPD.

T-cell-dependent airway and systemic inflammation triggers the progression of chronic obstructive pulmonary disease (COPD) and asthma. Retrospective studies suggest that simvastatin has anti-inflammatory effects in both diseases but it is unclear, which cell types are targeted. We hypothesized that simvastatin modulates T-cell activity. Circulating CD4+ and CD8+ T-cells, either pure, co-cultured with monocytes or alveolar macrophages (AM) or in peripheral blood mononuclear cells (PBMCs), were ex vivo activated towards Th1/Tc1 or Th2/Tc2 and incubated with simvastatin. Markers for Th1/Tc1 (IFNγ) and Th2/Tc2 (IL-5, IL-13) were measured by ELISA; with PBMCs this was done comparative between 11 healthy never-smokers, 11 current smokers without airflow limitation, 14 smokers with COPD and 11 never-smokers with atopic asthma. T-cell activation induced IFNγ, IL-5 and IL-13 in the presence and absence of accessory cells. Simvastatin did not modulate cytokine expression in pure T-cell fractions. ß-hydroxy-simvastatin acid (activated simvastatin) suppressed IL-5 and IL-13 in pure Th2- and Tc2-cells. Simvastatin suppressed IL-5 and IL-13 in Th2-cells co-cultivated with monocytes or AM, which was partially reversed by the carboxylesterase inhibitor benzil. Simvastatin suppressed IL-5 production of Th2/Tc2-cells in PBMCs without differences between cohorts and IL-13 stronger in never-smokers and asthma compared to COPD. Simvastatin induced IFNγ in Th1/Tc1-cells in PBMCs of all cohorts except asthmatics. Simvastatin requires activation in accessory cells likely by carboxylesterase to suppress IL-5 and IL-13 in Th2/Tc2-cells. The effects on Il-13 are partially reduced in COPD. Asthma pathogenesis prevents simvastatin-induced IFNγ up-regulation. Simvastatin has anti-inflammatory effects that could be of interest for asthma therapy.

Effect of lipoteichoic acid on IL-2 and IL-5 release from T lymphocytes in asthma and COPD.

Susceptibility to infections with gram-positive bacteria, which are an important trigger of exacerbations, is increased in COPD and asthma. Unraveling the underlying mechanisms may help developing therapeutic strategies to reduce exacerbation rates. The aim of this study was to evaluate the effects of lipoteichoic acid (LTA), a danger signal from gram-positive bacteria, on T cell cytokines related to bacterial infection defense in COPD and asthma. T cell populations within peripheral blood mononuclear cells (PBMCs) were ex-vivo activated towards T(H)2/T(C)2 subtypes and subsequently stimulated with LTA. IL-2 and IL-5 concentrations in cell culture supernatants were measured by ELISA comparative between non-smokers (NS), current smokers without airflow limitation (S), smokers with moderate to severe COPD and mild to moderate asthmatics (A) (each n=10). IL-2 and IL-5 baseline levels were without differences between the cohorts. After T cell activation, IL-2 and IL-5 releases were increased in all cohorts, however, for IL-2 this increase was significantly higher in S and by trend in COPD compared to the other groups. LTA time-dependently suppressed IL-2 release in NS, S and COPD but not in A. LTA reduced IL-5 release in COPD and A but not in NS and S. Summarized, LTA reduces T(H)2/T(C)2 cytokines indicating immunosuppressive effects, which are dysregulated in COPD and asthma. This implies a misguided response to gram-positive bacterial infections, which might help to explain the increased susceptibility to bacterial infections in COPD and asthma.

IL-5 release of CD4+ non-effector lymphocytes is increased in COPD--modulating effects of moxifloxacin and dexamethasone.

T-lymphocytes are crucial in chronic obstructive pulmonary disease (COPD) pathogenesis. Especially T(H)1-lymphocytes are involved in local and systemic inflammation in COPD, yet the role of T(H)2-mediated immune-responses in COPD pathogenesis is poorly understood. The objective of this study was to examine IL-5 expression in T(H)2-lymphocytes in smokers with and without COPD ex vivo compared with non-smokers and to evaluate the effects of bacterial endotoxin (lipopolysaccharide, LPS) as well as two drugs often used for treatment of COPD exacerbation, corticosteroids and moxifloxacin. CD4(+) lymphocytes were isolated from the peripheral blood of non-smokers (NS; n=11), current smokers without airflow limitation (S; n=11) and smokers with COPD (n=11). Baseline IL-5 release of CD4(+) T-lymphocytes was significantly increased in COPD compared to S and NS. After T-cell activation and differentiation into T(H)2-lymphocytes, IL-5 release increased without differences between the cohorts. LPS reduced IL-5 release of ex vivo generated T(H)2-lymphocytes without differences in all cohorts. Moxifloxacin and dexamethasone significantly reduced IL-5 release in T(H)2-lymphocytes in the absence and presence of LPS without differences between groups. In summary, our data indicate that IL-5 might contribute to systemic inflammation in smokers with COPD and that T(H)2-based immune responses might be suppressed in response to gram-negative bacterial infections independent from smoking and disease status. Dexamethasone and moxifloxacin both have T(H)2-immunmodulating effects.