A CENTRAL MECHANISM IS INVOLVED IN THE SECRETION OF ACTH IN RESPONSE TO IL-6 IN RATS - COMPARISON TO AND INTERACTION WITH IL-1-BETA

The cytokines interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha are known to be potent effectors of ACTH secretion. Some of the peripheral effects of IL-1beta appear to be related to the secretion of IL-6 induced by IL-1beta. Thus, we evaluated the effect of IL-6 on ACTH secretion and its interaction with IL-1beta. Rats received recombinant human (rhIL-6) or murine (rmIL-6) IL-6 through indwelling jugular cannulae. rhIL-6(200 ng or 2 mug/rat) produced peak plasma ACTH levels which were 3- to 4-fold greater than basal levels. rmIL-6 produced similar responses. Neither species of IL-6 affected plasma prolactin levels. Comparison of rhIL-1beta (200 ng) to rhIL-6 (200, 100 or 50 ng) showed that IL-6 elevated ACTH in a dose-dependent manner and that IL-1beta was significantly more effective. IL-1beta was also administered concomitantly with or 10 min after IL-6. Delivered together, IL-1beta (100, 30 or 10 ng) and IL-6 (100 ng) produced significantly higher ACTH levels than when given alone. This additivity was also evident when IL-6 was given 10 min prior to IL-1beta. The coadministration of IL-6 (2 mug) with corticotropin-releasing factor (CRF, 1 mug/kg, b.w.) also had an additive effect on ACTH secretion (at 20 min: 300 +/- 40 pg/ml for CRF; 320 +/- 83 pg/ml for IL-6; and 540 +/- 44 pg/ml for CRF+ IL-6), whereas a higher dose of CRF (10 mug/kg b.w.) yielded ACTH levels of 1,000 +/- 107 pg/ml at 20 min, with no further enhancement by IL-6. Incubation of pituitary cells with IL-6 alone (0. 1, 1.0 or 3.0 nM) produced a slight but significant stimulation of ACTH secretion within 2 h in response to the higher doses of IL-6 only (p < 0.05), but did not modify the effect of CRF in vitro. To determine if the action of IL-6 was at a site(s) within the brain, IL-6 (30 or 100 ng/0.5 mul) was injected into the third cerebroventricle of alert rats. 100 ng IL-6 elicited peak plasma ACTH levels (300 +/- 65 pg/ml) within 30 min; these were significantly higher than the buffer responses (90 +/- 25 pg/ml, p < 0.0 1), and lower than the responses to 30 ng IL-1beta (530 +/- 50 pg/ml, p < 0.001). 30 ng IL-6 was ineffective. Intraparenchymal injection of IL-6 (25 or 125 ng/0.4 mul) or IL-1beta (5 or 25 ng/0.4 mul) directly adjacent to the median eminence produced a significant elevation in the ACTH response to the higher dose of each at 30 min; 229 +/- 27 pg/ml after IL-1beta or 157 +/- 17 pg/ml after IL-6 compared to 64 +/- 12 pg/ml after buffer (p < 0.05). In contrast, after administration adjacent to the paraventricular nucleus, plasma ACTH levels were elevated only in response to the higher dose of IL-1beta: at 30 min, 206 +/- 31 pg/ml compared to buffer 117 +/- 17 pg/ml (p < 0.05). Thus, IL-6 is an ACTH secretagogue which may act within the brain, only in part at the level of the median eminence. Since the effect of IL-6 was additive with CRF, IL-6 appears to induce the secretion of CRF and, thereby, ACTH. IL-6, which was much less effective than IL-1beta was also additive with the latter which is known to be a CRF secretagogue.