PROINFLAMMATORY CYTOKINES AND THE NEUROENDOCRINE SYSTEM

The activation of the immune system is known to alter several brain functions that play crucial roles in controlling appropriate systemic immune responses. This concept of bilateral interaction between the immune and neural systems is best illustrated by the stimulatory influence of proinflammatory cytokines, in particular interleukin-1ß (IL-1ß), on the activity of neurons controlling the hypothalamic-pituitary adrenal (HPA) axis that is reflected by elevated plasma glucocorticoids, which are potent endogeneous inhibitors of the activated immune cells. Inappropriate plasma levels of glucocorticoids may contribute to deviant regulation of the immune response, indicating the importance in identifying and characterizing the mechanisms through which the local inflammatory process interacts with the neuroendocrine system. The long term objective of this project is to provide a better understanding of the sites of action and neuronal pathways mediating the influence of circulating proinflammatory cytokines on neuroendocrine functions altered during the immunogenic process. Important information will be gained about the cellular and molecular mechanisms solicited to trigger the transcription and release of neuropeptides responsible to control the activity of HPA axis and the appropriate secretion of glucocorticoids. Improvement in our knowledge of the basic mechanisms by which the immune system may access neuroendocrine functions in the central nervous system is of great importance not only because of the elegant concept of bi-directional communication described above, but also because these mechanisms may help us to define how disturbances in this interplay may contribute to the onset and progression of various pathologic states characterized by exaggerated immune responses.Transcriptional regulation of the lhrh gene.

Reproduction in mammals is critically dependent on the appropriate neurosecretion of luteinizing hormone-releasing hormone (LHRH) by the hypothalamus. We have shown that sophisticated molecular mechanisms are taking place within LHRH neurons during a specific period of the ovulation cycle (i.e. preovulatory LH surge), which, in turn, can be greatly altered by stress. Such effects of stress on the activity of these neurons have detrimental consequences on the reproductive system, including inhibition of sex steroid secretion and disruption of the ovulation cycle. The main objective of this project is to understand the neuronal and molecular mechanisms involved in the alteration of the LHRH neurons during ovulation and stressful conditions. Several techniques of molecular neurobiology, tract-tracing, secretion measurement, and a wide variety of experimental models, such as gene knock out mice, are currently being used in the laboratory. These experiments will clarify and will enhance our understanding of the regulation of LHRH neuronal activity in vivo, such as the signal transduction and transcription mechanisms involved in LHRH gene expression during the preovulatory LHRH and LH surge and the stress-related pathways capable of disrupting this process and causing infertility.

These projects are supported by the Medical Research Council of Canada and the Natural Sciences and Engineering Research Council of Canada, respectively.

Lacroix S, Rivest S (1998) Effect of acute systemic inflammatory response and cytokines on the transcription of the genes encoding cyclooxygenase enzymes (COX-1 and 2) in the rat brain. The Journal of Neurochemistry, 70(2): 452-466.