Men Have a Stronger Monocyte-Derived Cytokine Production Response upon Stimulation with the Gram-Negative Stimulus Lipopolysaccharide than Women: A Pooled Analysis Including 15 Study Populations

Abstract

The incidence of bacterial infections and sepsis, as well as the mortality risk from sepsis, is sex specific. These clinical findings have been attributed to sex differences in immune responsiveness. The aim of the present study was to investigate sex differences in monocyte-derived cytokine production response upon stimulation with the gram-negative stimulus lipopolysaccharide (LPS) using cytokine data from 15 study populations. Individual data on ex vivo cytokine production response upon stimulation with LPS in whole blood were available for 4,020 subjects originating from these 15 study populations, either from the general population or from patient populations with specific diseases. Men had a stronger cytokine production response than women to LPS for tumour necrosis factor-α, interleukin (IL)-6, IL-12, IL-1β, IL-1RA, and IL-10, but not for interferon-γ. The granulocyte-macrophage colony-stimulating factor production response was lower in men than in women. These sex differences were independent of chronological age. As men had higher monocyte concentrations, we normalized the cytokine production responses for monocyte concentration. After normalization, the sex differences in cytokine production response to LPS disappeared, except for IL-10, for which the production response was lower in men than in women. A sex-based approach to interpreting immune responsiveness is crucial.

Keywords: Blood; Cytokines; Gender; Innate immunity; Lipopolysaccharide; Sex.

Fig. 1

Forest plots of the ratios of men over women in cytokine production response of proinflammatory cytokines. For the populations listed, see Table 1.

Fig. 2

Forest plots of the ratios of men over women in cytokine production response of anti-inflammatory cytokines and cytokines that stimulate proinflammatory cytokine production. For the populations listed, see Table 1.

Fig. 3

Ratios of men over women in cytokine production response by chronological age. Scatter plots of the study populations from the general population stratified for age decade with meta-regression lines with 95% confidence intervals. A larger circle size indicates a higher precision of the estimate (circle size = 1/SE²). An estimate represents the mean of the ratio of men over women in cytokine production response for proinflammatory cytokines (tumour necrosis factor-α, interleukin [IL]-6, IL-12, and IL-1β) (n = 40) (a), anti-inflammatory cytokines (IL-1RA and IL-10) (n = 40) (b), interferon-γ (n = 17) (c), and granulocyte-macrophage co­lony-stimulating factor (n = 7) (d).