Gender specificity of altered human immune cytokine profiles in aging

Abstract

Cytokine generation by T cells and monocytes was determined for 50 subjects aged 65 yr or older and concurrently studied young subjects individually matched to each old subject for sex, race, and national origin. Highly significant differences between cytokine levels of old and young subjects all were gender specific. For T cells stimulated with anti-CD3 plus anti-CD28 antibodies, mean ratios of IFN-gamma generation for healthy old to young subjects were 0.22 for men (P<0.001; n=15) and 3.35 for women (P<0.001; n=13), and those of IL-17 were 0.30 for men (P<0.001) and no difference for women. CD8 T cells were the source of high IFN-gamma in healthy old women. For old men with an inflammatory or immune disease (n=10), mean old to young ratios of T-cell-generated IFN-gamma and IL-17 increased with disease severity up to 5.78 and 2.97 (both P<0.01), respectively, without changes for old women with similar diseases (n=12). For differentiated LPS-stimulated monocytes, old to young ratios of TNF-alpha and IL-6 generation were high only in women with immune or inflammatory disease (2.38, P<0.05 and 1.62, P<0.01, respectively), whereas ratios of IFN-gamma-evoked IP-10 chemokine were low in all groups. Alterations in immune cytokine profiles with aging show significant gender specificity.

Figure 1.

Dependence of T-cell generation of IFN-γ and IL-17 on the stimulating concentrations of anti-human CD3 + anti-human CD28 antibodies (TCR; μg/well) and of human IL-12 + IL-18 (ng/ml). Points and bars depict mean ± sd results of studies of T cells from 3 old and 3 young healthy (group I) female or male subjects. Significance of differences in values between young and old subjects after 3 d of incubation was calculated by a 2-sample t test. ⁺P < 0.05; *P < 0.01.

Figure 2.

Ratios of generation of IFN-γ and IL-17 by T cells from old healthy (group I) and young subjects. Stimuli were 1 μg/well each of anti-human CD3 + anti-human CD28 antibodies (TCR) and 50 ng/ml of IL-18 + 5 ng/ml of IL-12. Columns and bars depict mean ± sd values for supernates harvested at 2 d (hatched columns) and 3 d (open columns). Statistical significance of increases and decreases from the level of 1 (no difference between young and old) was calculated by the Mann-Whitney nonparametric test. ⁺P < 0.05; *P < 0.01; **P < 0.001.

Figure 3.

Relationships between immune-inflammatory status and the old-young ratios of generation of IFN-γ and IL-17 by T cells of subjects in groups I, IIA, and IIB. Stimuli, conditions, meanings of each type of column and bar, and statistical method and symbols denoting statistical significance of increases above and decreases below a ratio of 1 (no difference between age groups) are the same as in Fig. 2.

Figure 4.

Immune cellular bases for aging-associated alterations in generation of IFN-γ by immune cells of healthy old subjects. Columns and bars depict mean ± sd results of studies of NK/NKT cells and T cells from 3 healthy (group I) old female or male subjects and 3 young healthy female or male control subjects, with harvesting of supernates on d 2 (open bars) and d 3 (cross-hatched bars). Stimuli were 1 μg/well of anti-human CD3 + anti-human CD28 antibodies or combinations of 1 μg/well of anti-human CD3 antibody, 50 ng/ml of IL-18, 5 ng/ml of IL-2 or IL-12, and 50 ng/ml of phorbol myristate acetate (PMA). Significance of increases above and decreases below the 100% level, where values for young and old subjects would be the same, was calculated by a Mann-Whitney nonparametric test. ⁺P < 0.05; *P < 0.01.

Figure 5.

Ratios of generation of IL-6, TNF-α, and IP-10 chemokine by differentiated monocytes from healthy old (group I) and young subjects. Columns and bars depict mean ± sd values for supernates harvested at 6 h (hatched columns) and 24 h (open columns). Statistical significance of increases above and decreases below the level of 1 (no difference between young and old) was calculated by the Mann-Whitney nonparametric test. ⁺P < 0.05; *P < 0.01; **P < 0.001.

Figure 6.

Relationships between immune-inflammatory status and the old-young ratio of generation of IL-6, TNF-α, and IP-10 by differentiated monocytes of subjects in groups I, IIA, and IIB. Stimuli, conditions, and meanings of each type of column, bar, and symbol denoting statistical significance of increases above and decreases below the ratio of 1 (no difference between young and old) were the same as in Fig. 5.