In humans and sheep, endotoxin (LPS) administration results in increased growth hormone (GH) concentrations. To determine the role of cytokines in the effect of LPS on GH, sheep were challenged with IL-1 or TNF-. GH data were compared to results with LH where the major effects of LPS are known to act via the hypothalamus. Intracerebroventricular (icv) administration of IL-1 or TNF- did not alter plasma concentrations of GH. Endotoxin was then administered iv in combination with icv injection of either IL-1 antagonist (IL-1ra), TNF antagonist (sTNF-R1), or saline. Administration of LPS increased GH (P<0.0001), while co-administration of IL-1ra or sTNF-R1 icv did not alter GH response to LPS. In contrast, plasma concentrations of LH were profoundly inhibited by icv administration of either cytokine (P<0.03), but LH response to LPS was not altered by cytokine antagonists. Intravenous administration of either IL-1 or TNF- increased plasma concentrations of GH (P<0.0001). Administration of IL-1ra and sTNF-R1 iv prevented LPS-induced increases in GH. While LH was suppressed by high iv doses of IL-1 (P=0.0063), the antagonists did not alter LH response to LPS. In order to determine whether LPS might directly activate GH release, confocal microscopy revealed co-localization of CD14, the LPS receptor, with GH and to a lesser extent, LH and some PRL-containing cells, but not ACTH or TSH. These data are consistent with effects of LPS on GH secretion originating through peripheral cytokine presentation to the pituitary as well as a potential to act directly on selective populations of pituitary cells via CD14.