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Cytokines (IL-1, etc.) and the Stress (Hypothl/Pit/Adrenal) Axis

Vincent A Mazzarella vamg6792 at uxa.cso.uiuc.edu
Wed Apr 24 10:21:35 EST 1991

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.

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