ENDOTOXIN-INDUCED SUPPRESSION OF THE SOMATOTROPIC AXIS IS MEDIATED BYINTERLEUKIN-1-BETA AND CORTICOTROPIN-RELEASING FACTOR IN THE JUVENILERAT

This study extends the neuroendocrine role of central interleukin-1 be ta (IL-1 beta) during the stress of lipopolysaccharide (LPS) challenge to include inhibition of the somatotropic [GH-releasing hormone (GHRH )-somatostatin (SRIF)-GH] axis in juvenile male rats and clarifies the role of CRF in the mediation of LPS/IL-1-induced changes in GHRH and SRIF neurosecretion. The results of the in vivo component of this stud y demonstrated that LPS treatment (2.5 mg/kg twice daily for 5 days) c aused a significant attenuation of body weight gain for 2 days (2.4 +/ - 1.7% vs. 10.3 +/- 1.8% BW/day in saline controls; P < 0.05) and fail ure of catch-up growth thereafter even though a small transient suppre ssion of food intake returned to normal by the second of 4 days of tre atment. Associated with the first day of growth attenuation was an acu te suppression of all plasma GH parameters, including GH mass (area un der the curve, 1.972 +/- 0.1837 vs. 6.402 +/- 1.7 mu g/ml . 6 h for sa line controls; P < 0.05), in animals receiving an acute bolus of LPS, which was blocked by prior microinjection of IL receptor antagonist pr otein (IRAP) into the third ventricle. In contrast, GH parameters asso ciated with the second day of LPS-suppressed body weight gain were inc reased (GK mass, 9.4 +/- 2.2 vs. 3.5 +/- 0.5 mu g/ml . 4 h in saline c ontrols; P < 0.05). These increases were reversed after another 2 days of LPS treatment. In a series of in vitro experiments using medial ba sal hypothalamic (MEW) explants incubated with LPS [100 ng/ml alone or with 10(-7) M IRAP or 10(-6) M CRF antagonist (CRF-ANT)], GHRH releas e from MBH incubated with LPS was significantly greater than that in c ontrols (231 +/- 798 vs. 71 +/- 34% of baseline release; P < 0.05), an d this stimulation was antagonized by both IRAP and CRF-ANT. SRIF rele ase was significantly increased by incubation with LPS (163 +/- 28% vs . 97 +/- 20% of the baseline for controls; P < 0.05) and blocked (to 8 8 +/- 14% of the baseline) by IRAP, but not by CRF-ANT. Finally, when MBH explants were incubated with IL-1 beta (10(-9) M), there was a sig nificant inhibition of in vitro GHRH release (37.9 +/- 6.7% vs. 74.9 /- 16.6% for controls), which was reversed by IRAP and CRF-ANT, and a significant stimulation of SRIF release (168.7 +/- 37.5% vs. 98.0 +/- 11.6% for controls), which was reversed by IRAP, but not CRF-ANT. Thes e results demonstrate that LPS-induced neuroendocrine changes in the s omatotropic axis are mediated acutely at least in part by IL-1 beta, w hich acts to stimulate SRIF directly, and suggest that changes in GHRH release may be bimodal and involve IL-1 beta-induced increases in CRF . The ultimate suppression of GHRH by IL-1 and stimulation of SRIF by LPS and IL-1 would explain the acute suppression of plasma GH and redu ction of somatic growth in juvenile rats exposed to infectious materia ls.