Pharmacogenomics of neuroimmune interactions in human psychiatric disorders.
There is bidirectional communication between the brain and the immune system. Overproduction of interleukin-1beta (IL-1beta) leads to systemic inflammatory response syndrome (SIRS). The crucial role of IL-1beta in inflammation has been highlighted by studies performed in caspase-1 knockout mice (casp1(-/-)), transgenic mice that lack mature IL-1beta and survive lethal doses of lypopolysaccharide (LPS). We have previously shown that IL-1beta, its receptor IL-1 receptor I (IL-1RI) and caspase-1 are expressed within the brain. Moreover, we documented that peripherally injected LPS triggers a specific spatiotemporal pattern of expression of IL-1beta mRNA within the brain, suggesting that IL-1beta could be a major regulator of the central inflammatory cascade. Therefore, we studied brain transcriptional patterns that occur during LPS-induced SIRS in wild-type and casp1(-/-) mice. We showed patterns of gene expression in wild-type and casp1(-/-) mice that included differential expression of several genes, such as those for cytokines, chemokines, nitric oxide synthase 2 and cyclo-oygenase 2. A key component of the neuroimmune-endocrine axis that is increased by IL-1beta is corticotrophin releasing hormone (CRH). We found increased response to antidepressants in patients homozygous for the GAG haplotype of CRH receptor-1. Our results support the hypotheses that the CRH receptor-1 gene and possibly other genes in stress-inflammatory pathways are involved in the response to antidepressant treatment. Since dysregulation of the neuroimmune-endocrine axis appears to be one of the fundamental biological mechanisms that underlie psychiatric disorders, our findings might contribute to increase the understanding of the molecular pathways that are altered in these diseases.
Licinio
Julio
J
Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA. licinio@miami.edu
Mastronardi
Claudio
C
Wong
Ma-Li
ML
D000818:Animals; D023281:Genomics; D006801:Humans; D001523:Mental Disorders / Q000188:drug therapy* / Q000276:immunology*; D015213:Neuroimmunomodulation / Q000187:drug effects* / Q000235:genetics*; D011619:Psychotropic Drugs / Q000627:therapeutic use*
D011619:Psychotropic Drugs