Sex-specific Variation in Signaling Pathways and Gene Expression Patterns in Human Leukocytes in Response to Endotoxin and Exercise

While exercise effects on the immune system received increasing attention in recent years, it remains unclear to what extent gender and fluctuations in sex hormones during menstrual cycle influence immunological responses to exercise. Using a previously published microarray data set, we investigated mRNA changes induced through exhaustive exercise (half-marathon; pre-exercise and post-exercise [30 min, 3h, 24h], whole blood culture ± LPS (1h)) with a specific focus on sex differences (women in luteal phase vs men). Inflammation related pathways, TLRs, cytosolic DNA sensing and RIG-I like receptors were differentially activated between sexes in LPS-stimulated cultures. Genes differentially regulated between sexes included TNIP-1, TNIP-3, IL-6, HIVEP1, CXCL3, CCR3, IL-8 and CD69, revealing a bias towards less anti-inflammatory gene regulation in women compared to men. In addition, several genes relevant to brain function (OLIG2, TMEM106B, DDIT4, and KMO) showed differential activation between sexes. Some of these genes (e.g., KMO in women, DDIT4 in both sexes) potentially constitute neuroprotective mechanisms. These data reveal that the exercise-induced change in gene expression might be gender and menstrual cycle phase dependent. Factorial design comparing LPS and control treated blood samples of male and female athletes before and after a half-marathon at different timepoints (half-marathon; pre-exercise and post-exercise [30 min, 3h, 24h])