Clozapine inhibits Th1 cell differentiation and causes the suppression of IFN-γ production in peripheral blood mononuclear cells

Abstract

Antipsychotic drugs (APDs) are widely used to alleviate a number of psychic disorders and may have immunomodulatory effects. However, the previous studies of cytokine and immune regulation in APDs are quite inconsistent. The aim of this study was to examine the in vitro effects of different ADPs on cytokine production by peripheral blood mononuclear cells (PBMCs). We examined the effects of risperidone, clozapine, and haloperidol on the production of phorbol myristate acetate and ionomycin-induced interferon-γ (IFN-γ)/interleukin (IL)-4 in PBMCs by using intracellular staining. Real-time quantitative PCR and Western blot were used to further examine the expression changes of some critical transcription factors related to T-cell differentiation in antipsychotic-treated PBMCs. Our results indicated that clozapine can suppress the stimulated production of IFN-γ by 30.62%, whereas haloperidol weakly enhances the expression of IFN-γ. Differences in IL-4 production or in the number of CD4+ T cells were not observed in cells treated with different APDs. Furthermore, clozapine and risperidone inhibited the T-bet mRNA and protein expression, which are critical to Th1 differentiation. Also, clozapine can enhance the expression of Signal Transducer and Activator of Transcription 6 and GATA3, which are critical for the differentiation of Th2 cells. The results suggested that clozapine and haloperidol may induce different immunomodulatory effects on the immune system.

Adaptive Immunity in Schizophrenia: Functional Implications of T Cells in the Etiology, Course and Treatment

“…One of the underlying mechanisms is by regulating differentiation of T cell subsets. Atypical APDs like clozapine and risperidone were shown not only to effectively reduce production of IFN-γ for CD4(+) T cells in PBMC but also Th1 cell differentiation and T-bet expression Chen et al 2012). In contrast, typical APD like haloperidol increased the production of IFN-γ for CD4(+) T cells in PBMC, while decreased the differentiation of Th2 by inhibiting expression of GATA-3 .…”

Macrophage immunomodulation in chronic osteolytic diseases—the case of periodontitis

“…Clozapine has been shown to inhibit cellular production of IFN-in human PBMCs through binding of 5HT receptor. 136 5-HT can modulate Mac activation by inhibiting LPS-induced release of TNF-and IL-12, while stimulating IL-10 release. 137 Further, 5-HT was found to promote maintenance of rMacs through induction of gene expression associated with resolving activation and inhibition of genes associated with inflammatory activation.…”

“…Atypical APDs risperidone and clozapine bind to 5‐HT and dopamine receptors as well as adrenergic and other receptors. Clozapine has been shown to inhibit cellular production of IFN‐γ in human PBMCs through binding of 5HT receptor . 5‐HT can modulate Mac activation by inhibiting LPS‐induced release of TNF‐α and IL‐12, while stimulating IL‐10 release .…”

Gene expression analysis reveals schizophrenia-associated dysregulation of immune pathways in peripheral blood mononuclear cells

“…Another possibility is that medications are contributing toward the immune-associated gene expression signature. Indeed, a number of antipsychotics and antidepressants have been shown to display immunosuppressive and antiinflammatory effects (Chen et al, 2012;Drzyzga et al, 2006;Schmitt et al, 2005;Tynan et al, 2012). Nevertheless, the influence of antipsychotic medication on gene expression could not be determined due to the nature of this information being selfreported by the participants with schizophrenia rather than through medical records.…”