D-2-Hydroxyglutarate and L-2-Hydroxyglutarate Inhibit IL-12 Secretion by Human Monocyte-Derived Dendritic Cells.

Mutations in isocitrate dehydrogenase (IDH) or a reduced expression of L-2-hydroxyglutarate (HG)-dehydrogenase result in accumulation of D-2-HG or L-2-HG, respectively, in tumor tissues. D-2-HG and L-2-HG have been shown to affect T-cell differentiation and activation; however, effects on human myeloid cells have not been investigated so far. In this study we analyzed the impact of D-2-HG and L-2-HG on activation and maturation of human monocyte-derived dendritic cells (DCs). 2-HG was taken up by DCs and had no impact on cell viability but diminished CD83 expression after Lipopolysaccharides (LPS) stimulation. Furthermore, D-2-HG and L-2-HG significantly reduced IL-12 secretion but had no impact on other cytokines such as IL-6, IL-10 or TNF. Gene expression analyses of the IL-12 subunits p35/IL-12A and p40/IL-12B in DCs revealed decreased expression of both subunits. Signaling pathways involved in LPS-induced cytokine expression (NFkB, Akt, p38) were not altered by D-2-HG. However, 2-HG reprogrammed LPS-induced metabolic changes in DCs and increased oxygen consumption. Addition of the ATP synthase inhibitor oligomycin to DC cultures increased IL-12 secretion and was able to partially revert the effect of 2-HG. Our data show that both enantiomers of 2-HG can limit activation of DCs in the tumor environment.

Defining subjects at risk for psychosis: a comparison of two approaches.

The ability to detect individuals at high risk for developing schizophrenia before they express the disease will lead to targeted early intervention. It has been proposed that subjects at risk share a core deficit with people who already have schizophrenia. This includes cognitive impairment, affective symptoms, social isolation and decline in social functioning. In a sample of 104 help-seeking patients from a specialised outpatient clinic we investigated how well two different sets of criteria define the at-risk group and capture this core deficit. One set of criteria is the well-established ultra high-risk model of McGlashan et al. [McGlashan 2001 (SIPS) McGlashan, T. H., Miller, T. J., Woods, S. W., et al. (2001) Structured Interview for Prodromal Syndromes (Version 3.0, unpublished manuscript). New Haven, Connecticut: PRIME Research Clinic, Yale School of Medicine.]; the other criteria were those defined by Cornblatt et al. [Cornblatt, B., Lencz, T., Smith, C.W., Correll, C.U., Auther, A., Nakayama, E., 2003. The schizophrenia prodrome revisited: a neurodevelopmental perspective. Schizophr. Bull. 29, 633-651.]. There was considerable overlap in the two sets of criteria. However, when the basic symptoms of Klosterkötter [Klosterkötter, J., Hellmich, M., Steinmeyer, E.M., Schultze-Lutter, F., 2001a. Diagnosing schizophrenia in the initial prodromal phase. Arch. Gen. Psychiatry, 58, 158-164.] were included in the McGlashan et al. model, a more narrow and homogeneous group was defined.