Lactic acid delays the inflammatory response of human monocytes.

Lactic acid (LA) accumulates under inflammatory conditions, e.g. in wounds or tumors, and influences local immune cell functions. We previously noted inhibitory effects of LA on glycolysis and TNF secretion of human LPS-stimulated monocytes. Here, we globally analyze the influence of LA on gene expression during monocyte activation. To separate LA-specific from lactate- or pH-effects, monocytes were treated for one or four hours with LPS in the presence of physiological concentrations of LA, sodium lactate (NaL) or acidic pH. Analyses of global gene expression profiles revealed striking effects of LA during the early stimulation phase. Up-regulation of most LPS-induced genes was significantly delayed in the presence of LA, while this inhibitory effect was attenuated in acidified samples and not detected after incubation with NaL. LA targets included genes encoding for important monocyte effector proteins like cytokines (e.g. TNF and IL-23) or chemokines (e.g. CCL2 and CCL7). LA effects were validated for several targets by quantitative RT-PCR and/or ELISA. Further analysis of LPS-signaling pathways revealed that LA delayed the phosphorylation of protein kinase B (AKT) as well as the degradation of IκBα. Consistently, the LPS-induced nuclear accumulation of NFκB was also diminished in response to LA. These results indicate that the broad effect of LA on gene expression and function of human monocytes is at least partially caused by its interference with immediate signal transduction events after activation. This mechanism might contribute to monocyte suppression in the tumor environment.

Moderate Altitude Residence Reduces Male Colorectal and Female Breast Cancer Mortality More Than Incidence: Therapeutic Implications?

BACKGROUND: Living at moderate altitude may be associated with health benefits, including reduced mortality from male colorectal and female breast cancer. We aimed to determine altitude-dependent incidence and mortality rates of those cancers and put them in the context of altitude-associated lifestyle differences. METHODS: Incidence cases and deaths of male colorectal cancer (n = 17,712 and 7462) and female breast cancer (n = 33,803 and 9147) from altitude categories between 250 to about 2000 m were extracted from official Austrian registries across 10 years (2008-2017). Altitude-associated differences in health determinants were derived from the Austrian Health Interview Survey (2014). RESULTS: The age-standardized incidence and mortality rates of male colorectal cancer decreased by 24.0% and 44.2%, and that of female breast cancer by 6.5% and 26.2%, respectively, from the lowest to the highest altitude level. Higher physical activity levels and lower body mass index for both sexes living at higher altitudes were found. CONCLUSIONS: Living at a moderate altitude was associated with a reduced incidence and (more pronounced) mortality from colorectal and breast cancer. Our results suggest a complex interaction between specific climate conditions and lifestyle behaviours. These observations may, in certain cases, support decision making when changing residence.

Lactonization of the Oncometabolite D-2-Hydroxyglutarate Produces a Novel Endogenous Metabolite.

In recent years, onco-metabolites like D-2-hydroxyglutarate, which is produced in isocitrate dehydrogenase-mutated tumors, have gained increasing interest. Here, we report a metabolite in human specimens that is closely related to 2-hydroxyglutarate: the intramolecular ester of 2-hydroxyglutarate, 2-hydroxyglutarate-γ-lactone. Using 13C5-L-glutamine tracer analysis, we showed that 2-hydroxyglutarate is the endogenous precursor of 2-hydroxyglutarate-lactone and that there is a high exchange between these two metabolites. Lactone formation does not depend on mutated isocitrate dehydrogenase, but its formation is most probably linked to transport processes across the cell membrane and favored at low environmental pH. Furthermore, human macrophages showed not only striking differences in uptake of 2-hydroxyglutarate and its lactone but also in the enantiospecific hydrolysis of the latter. Consequently, 2-hydroxyglutarate-lactone may play a critical role in the modulation of the tumor microenvironment.