Juan C. Cambronero

Interleukin-1-Beta Induces Pituitary Adrenocorticotropin Secretion: Evidence for Glucocorticoid Modulation

Using an in vitro continuous perifusion system, the effects of interleukin-1 (IL-1) on adrenocorticotropin (ACTH) secretion at the pituitary level were investigated. On one hand, we observed that IL-1 beta increases ACTH secretion from perifused anterior pituitary cells in a dose-dependent manner, between 1.5 and 6 pM. This stimulatory action of IL-1 on ACTH was significantly attenuated by a short in vitro dexamethasone pretreatment. This fact suggests a regulatory glucocorticoid negative feedback analogous to that observed upon the pituitary action of corticotropin-releasing factor (CRF). We also examined the effect of simultaneous treatment with IL-1 and CRF. The results indicated that the effect of IL-1 resulted additive to the CRF-induced ACTH secretion. It is concluded that the anterior pituitary could be an important site of IL-1 action to activate the hypothalamic-pituitary-adrenocortical axis function, and that this action is under an inhibitory glucocorticoid regulation.

Role of arachidonic acid metabolism on corticotropin-releasing factor (CRF)-release induced by interleukin-1 from superfused rat hypothalami

The present work shows that the corticotropin-releasing factor (CRF)-releasing activity of interleukin-1 (IL-1) is partially inhibited by a phospholipase A2 (mepacrine) or a cyclooxygenase (indomethacin) inhibitor, but is not affected by inhibition of the lypoxygenase pathway with norhydroguaiaretic acid. These results indicate that the metabolism of arachidonic acid plays an important role as mediator of the effects of IL-1 on CRF release. It is also shown that products of the cyclooxygenase activity such as prostaglandins can stimulate CRF secretion by a direct action on the hypothalamus. Whereas PGE2 failed to induce increases on CRF release, PGF2 alpha stimulated in a dose-dependent manner (21-340 nM), the CRF release from continuous perifused hypothalami. It is suggested that PGF2 alpha could be involved as a messenger in the hypothalamic CRF secretion induced by IL-1.

Mutually antagonistic effects of corticosterone and prolactin on rat lymphocyte proliferation

The present study was designed to evaluate the immunological outcome resulting from experimental conditions involving different corticosterone and prolactin ratios in rats. One set of experiments was conducted to assess the effects of prolactin and corticosterone on the in vitro mitogen-induced proliferation of spleen lymphocytes from animals previously submitted to the manipulation of their glucocorticoid status throughout adrenalectomy (ADX) and/or exposure to acute stress. The results indicated that prolactin (5 x 10(-9) M) induced a significant increase in concanavalin A- (ConA) induced proliferation of splenocytes only from ADX-control, unstressed, rats. However, a lower dose of prolactin (10(-9) M) failed to influence lymphoproliferation. Corticosterone (2 x 10(-8) and 10(-7) M) induced a dose-dependent reduction in lymphocyte proliferation in all experimental groups. Further experiments were conducted to study the relative potency of prolactin to antagonize the in vitro corticosterone-induced suppression of ConA-stimulated lymphocytes. The results showed, on the one hand, that higher doses of prolactin (10(-8) and 5 x 10(-8) M) were effective in stimulating ConA-induced lymphocyte proliferation in control, undisturbed, rats. They also showed that when prolactin and corticosterone are simultaneously added to the cultures, the immunostimulatory effect induced by a dose of 10(-8) M of prolactin can either predominate over a weak suppressive action of corticosterone (2 x 10(-8) M) or totally antagonize to normal values a marked immunosuppression induced by a higher dose of corticosterone (10(-7) M). These data support the view that different ratios between prolactin and corticosterone concentrations can result in differential immunological outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of HPA hormones on adapted lymphocyte responsiveness to repeated stress

Acute stress-induced immune alterations can result in adapted function with prolonged exposure to the same stressor. The present study was designed to evaluate the possible role of the hypothalamic-pituitary-adrenocortical (HPA) axis on the adaptation of spleen lymphocyte responsiveness to repeated stress. For this purpose, we selected a stressful protocol (aversive auditory stimulation) that induced an initial suppression (1 day), followed by a return to control values with repeated application (4 days), of mitogen-induced lymphocyte proliferation. Because rats exposed to 4 days of noise sessions show enhanced adrenocorticotropin (ACTH) and corticosterone levels, we tested the possibility that adaptation of lymphoproliferation by repeated stress was due to a desensitization of splenic lymphocytes to stress-released HPA hormones. The results showed that corticotropin-releasing factor (10(-9) M) and corticosterone (5 x 10(-8) and 10(-7) M), as well as dexamethasone (10(-8), 5 x 10(-8), and 10(-7) M), significantly suppressed lymphoproliferation from both control and stressed rats in a similar way. ACTH (10(-9) and 5 x 10(-9) M) did not significantly influence Concanavalin-A-stimulated spleen lymphocytes. These data indicate that adaptation of lymphocyte proliferation by repeated noise stress occurs without accompanying alterations in lymphocyte responsiveness to HPA hormones.

Release of corticotropin-releasing factor from superfused rat hypothalami induced by interleukin-1 is not dependent on adrenergic mechanism

Interleukin-1 (IL-1) is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis. The hypothalamus seems to be the most important site of action of IL-1 on the HPA axis, inducing corticotropin-releasing factor (CRF) secretion. Catecholamines are important modulators of CRF secretion. In turn, IL-1 stimulates catecholamine release from the hypothalamus. In the present study, we examined the possible involvement of hypothalamic catecholamines in the effect of IL-1 beta on hypothalamic CRF secretion, by using an in vitro rat hypothalami continuous perifusion system. Neither in vivo pretreatment with an inhibitor of catecholamine synthesis nor in vitro exposure to alpha- or beta-adrenoceptor antagonists (phenoxybenzamine or propranolol, respectively) nor combination of both treatments altered the effect of IL-1 on CRF secretion from superfused hypothalami. These data indicate that catecholamines are not involved in the in vitro stimulatory action of IL-1 on hypothalamic CRF secretion.

Adrenalectomy does not change CRF secretion induced by interleukin-1 from rat perifused hypothalami

Interleukin-1 (IL-1) is a potent hypothalamic-pituitary-adrenal (H-P-A) axis activator. The hypothalamus is considered one of the main sites of action of IL-1 on the H-P-A axis, inducing CRF secretion, which is modulated by glucocorticoids. Glucocorticoids, which modulate CRF release by a negative feedback inhibition, have been postulated to exert a permissive action on the IL-1 effect on CRF secretion. Using a continuous perifusion system of rat hypothalami, the results of the present study indicate that at the same concentrations, IL-1 beta exerted a more potent effect than IL-1 alpha stimulating CRF secretion. The increase in hypothalamic CRF release induced by IL-1 was rapidly inhibited by both dexamethasone and corticosterone. However, adrenalectomy 2 or 8 days before did not modify CRF secretion induced by IL-1 from the in vitro perifused hypothalami. These data indicate that IL-1 does not seem to induce CRF secretion by interfering with an impeding action of glucocorticoids, although the cytokine effect is negatively modulated by corticosteroids.