Age-associated defect in human TLR-1/2 function

J Immunol. 2007 Jan 15;178(2):970-5. doi: 10.4049/jimmunol.178.2.970.

Abstract

The effects of aging on human TLR function remain incompletely understood. We assessed TLR function and expression in peripheral blood monocytes from 159 subjects in 2 age categories, 21-30 and >65 years of age, using a multivariable mixed effect model. Using flow cytometry to assess TLR-induced cytokine production, we observed a substantial, highly significant defect in TLR1/2-induced TNF-alpha (p = 0.0003) and IL-6 (p < 0.0001) production, in older adults compared with young controls. In contrast to findings in aged mice, other TLR (including TLR2/6)-induced cytokine production appeared largely intact. These differences were highly significant even after correcting for covariates including gender, race, medications, and comorbidities. This defect in TLR1/2 signaling may result from alterations in baseline TLR1 surface expression, which was decreased by 36% in older adults (p < 0.0001), whereas TLR2 surface expression was unaffected by aging. Production of IL-6 (p < 0.0001) and TNF-alpha (p = 0.003) after stimulation by N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-Cys-[S]-Ser1-[S]-Lys(4) trihydrochloride was strongly associated with TLR1 surface expression. Diminished TLR1/2 signaling may contribute to the increased infection-related morbidity and mortality and the impaired vaccine responses observed in aging humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aging / physiology*
  • Cell Membrane / metabolism
  • Female
  • Humans
  • Interleukin-6 / biosynthesis
  • Male
  • Middle Aged
  • Toll-Like Receptor 1 / metabolism*
  • Toll-Like Receptor 2 / metabolism*
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Interleukin-6
  • Toll-Like Receptor 1
  • Toll-Like Receptor 2
  • Tumor Necrosis Factor-alpha