HYPOPHYSECTOMY INHIBITS THE SYNTHESIS OF TUMOR-NECROSIS-FACTOR-ALPHA BY RAT MACROPHAGES - PARTIAL RESTORATION BY EXOGENOUS GROWTH-HORMONE OR INTERFERON-GAMMA

We recently demonstrated that GH and interferon-gamma (IFN-gamma) act in a similar manner to prime macrophages in vitro and in vivo for enhanced superoxide anion release. In this report we investigated the physiological role of the pituitary gland and GH in in vivo priming of resident peritoneal macrophages for the synthesis of tumor necrosis factor-alpha (TNF-alpha) in vitro. Compared to normal rats, hypophysectomized animals had an 83% reduction in macrophage production of TNF-alpha after in vitro stimulation with lipopolysaccharide. Sham operation had no significant effect on the ability of macrophages to secrete TNF-alpha in response to lipopolysaccharide. Both native pituitary-derived porcine GH (48-mu-g/rat.9 days) and native pituitary-derived rat GH (96-mu-g/rat.9 days) more than tripled the in vitro production of TNF-alpha by macrophages from hypophysectomized rats (342 and 658 vs. 112 U/mg protein for placebo-treated rats, respectively). Each of these preparations of GH also increased growth more than 6-fold in hypophysectomized rats (32 and 30 g vs. 5g in placebo controls). Heat inactivation of native pituitary-derived porcine GH significantly reduced its in vivo ability to augment both TNF-alpha synthesis by macrophasges and body growth. Recombinant rat IFN-gamma (2000 U/rat.9 days) more than tripled the production of TNF-alpha by macrophages from hypophysectomized rats (343 vs. 112 U/mg protein). In contrast to it in vivo effects, addition of GH in vitro to macrophages from hypophysectomized rats did not prime these cells for the synthesis of TNF-alpha, indicating an indirect mechanism of action for GH. To further test the biological relevancy of GH with respect to synthesis of TNF-alpha, hemorrhagic necrosis of TNF-alpha-sensitive murine methyl-cholanthrene-induced tumors was assessed pituitary-intact mice. Native porcine GH (133-mu-g/mouse.7 days) significantly augmented both the necrosis to tumor ratio and the hemorrhage to tumor ratio. These findings establish the physiological relevance of the pituitary gland and GH in the priming of macrophages for TNF-alpha synthesis.