A systemic defect in Toll-like receptor 4 signaling increases lipopolysaccharide-induced suppression of IL-2-dependent T-cell proliferation in COPD.
The susceptibility to bacterial infections is increased in chronic obstructive pulmonary disease (COPD). This promotes exacerbations. IL-2 triggers CD4(+)/Th1-cell proliferation, which is important for infection defense. Bacterial endotoxin (LPS) activates MyD88/IRAK and TRIF/IKKε/TBK1 pathways via Toll-like receptor-4 (TLR4) in Th1 cells. Systemic defects in TLR pathways in CD4(+)/Th1 cells cause an impairment of IL-2-dependent immune responses to bacterial infections in COPD. Peripheral blood CD4(+) T cells of never smokers, smokers without COPD, and smokers with COPD (each n = 10) were ex vivo activated towards Th1 and stimulated with LPS. IL-2, MyD88, and TRIF expression, and cell proliferation was analyzed by ELISA, quantitative RT-PCR, and bromodeoxyuridine (BrdU) and trypan blue staining comparative among the cohorts. IL-2 release from activated T cells was increased in COPD vs. smokers and never smokers. LPS reduced IL-2 expression and T-cell proliferation. These effects were increased in COPD vs. never smokers and inversely correlated with FEV1 (%predicted). The MyD88/TRIF ratio was decreased in Th1 cells of COPD. The suppression of IL-2 by LPS was abolished by MyD88/IRAK blockade in never smokers but by TRIF/IKKε/TBK1 blockade in COPD. Moxifloxacin restored IL-2 expression and T-cell proliferation in the presence of LPS by blocking p38 MAPK. The increased IL-2 release from Th1 cells in COPD might contribute to airway inflammation in disease exacerbations. A switch from MyD88/IRAK to TRIF/IKKε/TBK1 signaling amplifies the suppression of IL-2-dependent proliferation of CD4(+) T cells by LPS in COPD. This molecular pathology is of systemic origin, might impair adaptive immune responses, and could explain the increased susceptibility to bacterial infections in COPD. Targeting TLR4-downstream signaling, for example, with moxifloxacin, might reduce exacerbation rates.
Medical Clinic III for Pneumology, Allergology, Sleep and Respiratory Medicine, Bergmannsheil University Hospital, Bochum, Germany; and juergen.knobloch@ruhr-uni-bochum.de.
Jürgen
J
Knobloch
Medical Clinic III for Pneumology, Allergology, Sleep and Respiratory Medicine, Bergmannsheil University Hospital, Bochum, Germany; and.
Sarah-Jane
SJ
Chikosi
Medical Clinic III for Pneumology, Allergology, Sleep and Respiratory Medicine, Bergmannsheil University Hospital, Bochum, Germany; and.
Sarah
S
Yanik
Department of Medical Microbiology and Hygiene, University of Lübeck, Lübeck, Germany.
Jan
J
Rupp
Medical Clinic III for Pneumology, Allergology, Sleep and Respiratory Medicine, Bergmannsheil University Hospital, Bochum, Germany; and.
David
D
Jungck
Medical Clinic III for Pneumology, Allergology, Sleep and Respiratory Medicine, Bergmannsheil University Hospital, Bochum, Germany; and.
Andrea
A
Koch
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D024841:Fluoroquinolones / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007376:Interleukin-2 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D000077266:Moxifloxacin; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D018417:Th1 Cells / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; C508594:IL2 protein, human; D007376:Interleukin-2; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases; D000077266:Moxifloxacin
CD4+/Th1 lymphocytes; COPD exacerbation; Toll-like receptor signaling; lipopolysaccharide