A systemic defect in Toll-like receptor 4 signaling increases lipopolysaccharide-induced suppression of IL-2-dependent T-cell proliferation in COPD

Am J Physiol Lung Cell Mol Physiol. 2016 Jan 1;310(1):L24-39. doi: 10.1152/ajplung.00367.2014. Epub 2015 Oct 23.

Abstract

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.

Keywords: CD4+/Th1 lymphocytes; COPD exacerbation; Toll-like receptor signaling; lipopolysaccharide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Cell Proliferation* / drug effects
  • Fluoroquinolones / pharmacology*
  • Humans
  • Inflammation / immunology
  • Interleukin-2 / metabolism*
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology*
  • Moxifloxacin
  • Pulmonary Disease, Chronic Obstructive / genetics
  • Pulmonary Disease, Chronic Obstructive / immunology
  • Pulmonary Disease, Chronic Obstructive / metabolism*
  • Signal Transduction* / drug effects
  • Th1 Cells / immunology
  • Toll-Like Receptor 4 / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Anti-Bacterial Agents
  • Fluoroquinolones
  • IL2 protein, human
  • Interleukin-2
  • Lipopolysaccharides
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • p38 Mitogen-Activated Protein Kinases
  • Moxifloxacin