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Title: MECHANISMS UNDERLYING GROWTH HORMONE EFFECTS IN AUGMENTING NITRIC OXIDE PRODUCTION AND PROTEIN TYROSINE NITRATION DURING ENDOTOXIN CHALLENGE

Author
item Elsasser, Theodore
item Kahl, Stanislaw
item Li, Congjun - Cj
item SARTIN, J. - AUBURN UNIVERSITY
item MACLEOD, C. - UNIV. CAL.SAN DIEGO
item NICHOLSON, B. - UNIV. CAL.SAN DIEGO

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/16/2004
Publication Date: 3/25/2004
Citation: Elsasser, T.H., Kahl, S., MacLeod, C., Nicholson, B., Sartin, J.L., Li, C. 2004. Mechanisms underlying growth hormone effects in augmenting nitric oxide production and protein tyrosine nitration during endotoxin challenge. Endocrinology. 145(7):3413-3423.

Interpretive Summary: Nitric oxide is an important part of the immune response because or its ability to coordinate communication between different tissues in the body as well as regulate blood flow and destroy pathogens. Growth hormone has potential to affect immune response to infection in a positive way because of its capability of increasing protein retention and improving the efficiency of function of some parts of the immune system. We conducted several experiments to determine how GH might affect the production of nitric oxide in association with an immune challenge. Our results indicated for the first time that GH has the capability of increasing nitric oxide production during an immune challenge. At the level of immune challenge we used, we could account for all or the effect through the vascular form of the enzyme that makes nitric oxide in the liver, and not the form used by macrophages to kill bacteria. Also, we showed that a large part of the effect of GH may be related to its capacity to decrease certain other enzymes that compete with the nitric oxide enzyme and thus make mote substrate available to the nitric oxide pathway. The results suggest that a part of the immune effect of GH may come from its ability to change nitric oxide production.

Technical Abstract: The aim of present study was to define the effects of GH administration on major components of the arginine use and the NO generating cascade that could account for previously observed increased NO and nitrated protein generation following an immune challenge. Female calves were assigned to + or -GH treatment (100 'g/kg recombinant bovine GH, im, daily x 12 d) and + or ' low-level LPS challenge (E. coli, 055:B5, 2.5 'g/kg, iv). Blood plasma (hourly after LPS; (n=6/time point) was obtained for estimation of NO changes as measured [NO2-] + [NO3-]. Liver tissue (transcutaneous biopsy; 0, +3, +6 and +24 hours relative to LPS) was collected for mRNA content of the arginine amino acid transporter CAT-2 (RT/PCR), and estimates of cNOS and iNOS activity (differential enzyme assay) and protein content (western blot), and arginase activity. Liver protein nitration, measured by quantitative immunohistochemical localization using anti-nitrotyrosine antibody, was elevated more than 10-fold after LPS challenge and further 2-fold greater in animals treated with GH prior to LPS. GH treatment was associated with an increase in plasma NOx- (P<0.05) after LPS 27% greater than that measured in calves not treated with GH. LPS increased liver CAT-2 mRNA content 6h (P<0.01) after LPS; GH was associated with a 24% reduction (P<0.05) in CAT-2 mRNA content at the measured peak of response. NOS enzyme activities were increased 140% (cNOS) at +3 hours and 169% (iNOS) at 6 hours, respectively, after LPS in +GH animals (P<0.05) compared to -GH animals; however, iNOS activity was less than 0.9% of the enzyme activity of cNOS. The data indicate that GH treatment prior to immune challenge increases liver protein tyrosine nitration and further suggest that the increased NO response to the imposed low-level LPS challenge of GH-treated animals is predominantly driven through modulation of cNOS activity rather than enzyme content. In that arginase-driven urea production from arginine was 3-4 orders of magnitude greater than the use of arginine to form NO via total NOS activity after LPS, minor changes in arginase activity as affected by GH treatment might similarly be an NO response control point where GH could shift the acute availability of arginine towards increased NO production.