Author(s): Knobloch J, Schild K, Jungck D, Urban K, Mller K,
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Abstract RATIONALE: The increased susceptibility to bacterial infections in chronic obstructive pulmonary disease (COPD) is critical for exacerbations. Toll-like receptor-4 (TLR4) detects bacteria via LPS and induces IFN-γ-based immune responses. The direct responsiveness of Th1 lymphocytes to LPS is disputed because they lack surface expression of the TLR4 coreceptor CD14. OBJECTIVES: We hypothesized that the Th1-mediated adaptive immune response to bacterial infections is impaired in COPD. METHODS: LPS-induced TLR4 expression and IFN-γ release in and from ex vivo-generated Th1 cells was compared among nonsmokers (n = 14), smokers without COPD (n = 13), and smokers with COPD (n = 25) via quantitative reverse transcription polymerase chain reaction, Western blot, and ELISA. TLR4 transfection experiments were performed to functionally link receptor to IFN-γ dysregulation in COPD. MEASUREMENTS AND MAIN RESULTS: Short-chain LPS from Salmonella species and nontypeable Haemophilus influenzae and nontypeable Haemophilus influenzae whole-cell extract all induced TLR4 expression via TLR4/MyD88/IRAK/mitogen-activated protein-kinase signaling and IFN-γ release via TLR4/TRIF/IKKε/TBK1 signaling in Th1 cells of nonsmokers. These effects were all impaired in smokers with and without COPD. The LPS responses were partially dependent on soluble CD14 and correlated positively to lung-function parameters but negatively to cigarette smoking (pack-years). Endogenous MyD88/IRAK signaling antagonists were up-regulated in Th1 cells of smokers and COPD, and TLR4 overexpression in Th1 cells of COPD restored LPS-dependent IFN-γ release. CONCLUSIONS: Th1 cells directly respond to short-chain LPS. Cigarette smoking suppresses Th1-mediated immune responses to gram-negative bacterial infections by interfering with MyD88/IRAK signaling thereby reducing LPS-induced TLR4 expression. This can explain the increased susceptibility to bacterial infections in COPD. Targeting TLR signaling might be useful to reduce exacerbation rates.
This article was published in Am J Respir Crit Care Med
and referenced in Journal of Bioanalysis & Biomedicine