vamg6792@uxa.cso.uiuc.edu (Vincent A Mazzarella) (04/24/91)
The following is a one page synopsis of a recent one-hour seminar. The impressions are my own and do not reflect accuracy of the facts contained in the presentation. Corrections and discussion are welcomed. When the body is injured, self antigens can be altered at the site of damage to look foreign. If the immune system were not modulated, these foreign looking antigens might set off further damage by autoimmune processes. The body thus needs a method to modulate immune responses. When the body is stressed in ways other than just trauma, the immune system is depressed. What is the mechanism of this suppression? Interleukin-1 may be the link between immune responses and the stress axis. By stimulating ACTH secretion, it indirectly causes glucocorticoid secretion, which is well known to suppress immune function. Lipopolysaccharide (LPS) injected into a rat elicits an increase in ACTH. But it is found that interleukin-1 (IL-1) will cause an increase in ACTH levels. In cultered anterior pituitary cells, however, neither elicits ACTH secretion. The IL-1 does, however, cause an increase in CRF release in the hypothalamus, even though no receptors for IL-1 have been demonstrated in the hypothalamus (but have been demonstrated in the hippocampus, which projects to the hypothalamus). CRF (corticotropin releasing factor) stimulates the anterior pit. cells to secrete ACTH. Antibodies to CRF blocks the IL-1 induced ACTH secretion, indicating the essential intermediary role of CRF. On the gonadal axis side of the picture, stress suppresses the pulsatile LH release normally seen in rats. IL-1 also suppresses the LH surge. Macrophages in the gonads produce IL-1 at ovulation in cycling rats, which may account for the increase in temperature at ovulation. These interleukins may then stimulate CRF release, which in turn inhibits GnRH action in causing LH release. Alternatively, IL-1 may play a direct role in directly altering gonadal receptor number or sensitivity to pituitary reproductive hormone. The role of opiate receptors is unclear. Peripheral adrenergic blockade with prazocin (alpha-1) and propanolol (beta-1,2) did not reduce the effects of IL-1, indicating that it does not mediate the effects. IL-1 receptor localization shows a similar pattern to opiate receptor localization, suggesting a possible relation between opiate action and the IL-1 action. Also unclear is how the relatively large and lipid-impermeable cytokines (e.g. IL-1) cross the blood-brain barrier. Perhaps prostaglandins, especially from astrocytes (which have a large PG producing function), mediate the effect of IL-1 on the CRF producing cells. However, indomethacin, which inhibits the cyclo-oxygenase that produces the PGs, does not completely inhibit IL-1's effects, suggesting that another route must also play a role. From a seminar at Univ. of Illinois, Spring 1991: Cytokines and the Hypothal-Pit-Gonadal and Hypothal-Pit-Adrenal Axes -- Catherine Rivier, Salk Inst. -- Vincent Mazzarella College of Medicine, Neuroscience Program University of Illinois, Urbana-Champaign e-mail: mazz@vmd.cso.uiuc.edu