Impact of antipsychotic drug administration on the expression of nuclear receptors in the neocortex and striatum of the rat brain.

We have recently shown that the expression of the nerve growth factor-inducible gene B (NGFI-B, or Nur77), a transcription factor belonging to the large ligand-activated nuclear receptor family, is modulated by antipsychotic drugs in the rat forebrain. In the present work, we have investigated the impact of antipsychotic drugs on a series of transcription factors also belonging to the nuclear receptor family. The receptors investigated include retinoid X receptor (RXR), thyroid hormone receptor (TR), retinoic acid receptor (RAR), RAR-related orphan receptor (RZR) and Rev-erb receptor isoforms in addition to the NGFI-B transcript. We have used in situ hybridization to monitor their mRNA levels after acute and chronic antipsychotic drug administration. RZRbeta and NGFI-B mRNA levels are down-regulated after chronic haloperidol or clozapine treatment in the primary somatosensory cortex. The TRbeta1 isoform mainly expressed in the cingulate cortex is modulated only after chronic clozapine treatment, whereas TRalpha isoform mRNAs are modulated by both antipsychotics in the cingulate cortex and nucleus accumbens shell; two brain areas associated with limbic functions. The RXRgamma1 isoform, mostly expressed in the dorsolateral portion of the striatum is modestly affected by antipsychotics. Modulation of the expression of transcription factors belonging to the ligand-activated nuclear receptor family by antipsychotics represents an additional molecular event in the mechanism of action of these drugs. We suggest that modification of the pattern of transcription factor expression may play a role in long-term cellular responses to these drugs.

CD40- and HLA-DR-mediated cell death pathways share a lot of similarities but differ in their use of ADP-ribosyltransferase activities.

CD40 and HLA-DR molecules are two major components of the immune system, and their engagement on several cell types leads to various cellular events that modulate cell function. In this study, we demonstrate that signaling via these molecules leads to a rapid B cell death. CD40-mediated cell death was mainly observed in Epstein-Barr virus (EBV)-transformed B cell lines, whereas, HLA-DR-induced response can be triggered in normal activated B cells as well as in EBV-transformed B cell lines. Cell death induced via both molecules does not require de novo protein synthesis, but involves the integrity of the cytoskeleton. The sensitivity of CD40- and HLA-DR-mediated cell death to various inhibitors is very similar to that previously reported for tumor necrosis factor receptor (TNFR)- and Fas-triggered apoptosis; however, caspases leading to poly(ADP-ribose) polymerase cleavage are not implicated in this response. Both B cell death forms do not involve Fas-Fas ligand and TNF-TNFR systems, but require LFA-1-independent cell-cell interactions mediated by still undefined molecules. Although CD40- and HLA-DR-mediated cell death appears to follow a common pathway, inhibitors of poly- and mono-ADP-ribosyltransferase activity differentially affect these responses. Defining the molecules involved in CD40- and HLA-DR-mediated death will provide a possible interrelation between the different B cell death programs that can lead to a better comprehension of regulation of B cell functions.

Triggering HLA-DR molecules on human peripheral monocytes induces their death.

Although engagement of MHC class II molecules on human monocytes triggers various cellular events, their possible role in monocyte death is yet unknown. We demonstrate that ligation of MHC class II on primary monocytes induces a rapid cell death that has all the characteristics of monocyte apoptosis, does not require de novo protein synthesis, is independent from both Fas and TNF-alpha systems, and is not rescued by ligation of CD40. However, cell-cell interactions that involve the beta2-integrin CD18 seem to be critical for the execution of this monocyte death. Priming monocytes with IFN-gamma enhances significantly their HLA-DR-mediated death whereas LPS treatment effectively reverses this death process. Thus, our results describe the MHC class II molecules, in particular HLA-DR, as mediators of monocyte death and suggest that this novel pathway of monocyte death might have an important role in controlling the outcome of inflammatory process and the regulation of monocyte hemostasis.