Supplementary Material for: 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

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.

细菌感染与脓毒症（sepsis）的发病率、以及脓毒症相关死亡风险均存在性别特异性差异。这类临床发现被归因于免疫应答能力的性别差异。本研究旨在利用来自15个研究队列的细胞因子数据，探究革兰氏阴性菌刺激物脂多糖（lipopolysaccharide, LPS）刺激下，单核细胞源细胞因子生成应答的性别差异。

本研究纳入的4020名受试者均来自上述15个研究队列，其中既包括普通人群个体，也涵盖特定疾病患者人群，所有受试者均具备全血经LPS刺激后的离体细胞因子生成应答的个体水平数据。

相较于女性，男性在肿瘤坏死因子-α（tumour necrosis factor-α）、白细胞介素（interleukin, IL）-6、IL-12、IL-1β、白细胞介素1受体拮抗剂（interleukin 1 receptor antagonist, IL-1RA）以及IL-10的生成应答上对LPS的反应更强，但干扰素-γ（interferon-γ）的生成应答未表现出此类性别差异。而男性的粒细胞-巨噬细胞集落刺激因子（granulocyte-macrophage colony-stimulating factor）生成应答则低于女性。

上述性别差异不受实足年龄的影响。鉴于男性的单核细胞浓度更高，我们针对单核细胞浓度对细胞因子生成应答进行了标准化处理。标准化后，除IL-10的生成应答仍低于女性外，其余细胞因子对LPS的生成应答的性别差异均不复存在。

基于性别的免疫应答解读方法至关重要。