Testosterone suppresses phospholipase D, causing sex differences in leukotriene biosynthesis in human monocytes.

Sex disparities in inflammation have been reported, but the cellular and molecular basis for these discrepancies is unknown. Monocytes are central effector cells in immunity and possess high capacities to produce proinflammatory leukotrienes (LTs). Here, we investigated sex differences in the activation of 5-lipoxygenase (5-LO), the key enzyme in LT biosynthesis, in human peripheral monocytes. In cells from females, 5-LO product formation was 1.8-fold higher than in cells from males, as evaluated by HPLC. When female monocytes were resuspended in plasma from males, 5-LO products were significantly lower than in female plasma. Interestingly, 5α-dihydrotestosterone (5α-DHT, 10 nM) repressed LT synthesis in female cells down to the levels observed in males, while estradiol (100 nM) was without effect, and progesterone (100 nM) caused only a slight inhibition. 5α-DHT (10 nM) caused ERK phosphorylation and inhibition of phospholipase D (PLD), as evaluated by Western blot and measurement of PLD activity via radioenzymatic diacylglyceride (DAG) and nonradioactive choline assays. Accordingly, PLD activity and DAG formation were 1.4- to 1.8-fold lower in male vs. female monocytes connected to increased ERK phosphorylation. Our data indicate that ERK activation by androgens in monocytes represses PLD activity, resulting in impaired 5-LO product formation due to lack of activating DAGs.

Edaphic and Phytochemical Factors as Predictors of Equine Grass Sickness Cases in the UK.

BACKGROUND: Equine dysautonomia or equine grass sickness (EGS), as it is more commonly known, is a usually fatal disease of equids of uncertain etiology, although associated with grazing, that affects the autonomic and enteric nervous system. Lowered gastrointestinal motility, leading to paralysis of the gut, is one of the main symptoms of EGS. Previous studies have implicated anaerobic bacteria, notably Clostridium botulinum, but what triggers the severe bacterial infestations remains enigmatic. We hypothesized that a detailed comparison of soil mineral and botanical composition of EGS and control sites would yield new insights into the causation of the disease. RESULTS: Between March 2007 and September 2008, soil, plant, and water samples from a total of 23 EGS sites and 11 control sites were studied. Metal and non-metal element levels of the soil and herbage samples were assessed. Significantly, EGS sites had higher levels of soil nitrogen, and significantly higher levels of iron, lead, arsenic, and chromium in the herbage. Toxic Ranunculus spp. (buttercups) were found in abundance at every EGS site, making ingestion plausible. Conversely, neurotoxin-producing cyanobacteria were not found in any of the water samples analyzed. CONCLUSIONS: The significantly higher levels of iron and heavy metals found in herbage growing in EGS sites, in addition to toxic Ranunculus species, suggest that previously unknown triggers are involved in a multi-factorial EGS etiology. Our results also show that cyanobacteria on the other hand, are unlikely to be a factor in EGS. Consequently, the concomitant presence of two (or more) factors could be the trigger for an outbreak of EGS.