Age-Associated Defect in Human TLR-1/2 Function

Journal of Immunology - Tập 178 Số 2 - Trang 970-975 - 2007
David van Duin1,2, Subhasis Mohanty1,2, Venetta Thomas2,3, Sandra Ginter2,4, Ruth R. Montgomery2,3, Erol Fikrig2,3, Heather Allore2,4, Ruslan Medzhitov2,5, Albert C. Shaw1,2
1Infectious Diseases, and
2Sections of
3Rheumatology
4‡Department of Internal Medicine and Program on Aging, and
5Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520

Tóm tắt

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-α (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-α (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.

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Journal of Immunology

Tập 178 Số 2

970-975

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