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Caveolae Nitration of Janus Kinase-2 at the ₁₀₀₇Y-₁₀₀₈Y Site: Coordinating Inflammatory Response and Metabolic Hormone Readjustment within the Somatotropic Axis

Agricultural Research Service (T.H.E., S.K., C.-J.L., W.M.G.), U.S. Department of Agriculture, Beltsville, Maryland 20705; Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine (J.L.S.), Auburn University, Auburn, Alabama 36849; and Department of Neuroanatomy and Cellular Biology (J.R.), Cajal Institute, E-28002 Madrid, Spain

Address all correspondence and requests for reprints to: Ted H. Elsasser, Growth Biology Laboratory, U.S. Department of Agriculture, Agricultural Research Service, B-200, Room 201, BARC-east, Beltsville, Maryland 20705. E-mail: elsasser{at}anri.barc.usda.gov.

Life-threatening proinflammatory response (PR) induces severe GH resistance. Although low-level PR is much more commonly encountered clinically, relatively few studies have investigated the accompanying change in GH signal transduction progression and, in particular, the impact of low-level PR on Janus kinase (JAK)-2. Using a low-level, in vivo endotoxin [lipopolysaccharide (LPS)] challenge protocol, we demonstrated that the liver tissue content of JAK2 declined 24 h (62%, P < 0.02) after LPS and that tyrosine-nitrated JAK2 could be immunoprecipitated from post-LPS liver biopsy homogenates. With antibodies developed to probe specifically for nitration at the ₁₀₀₇Y-₁₀₀₈Y phosphorylation epitope of JAK2, we demonstrated that the nitrated ₁₀₀₇Y-₁₀₀₈Y-JAK-2 (nitro-JAK2) coimmunoprecipitated with caveolin-1 and ₁₁₇₇phospho-SER-endothelial nitric oxide synthase when post-LPS liver homogenates were treated with anticaveolin-1 and protein A/G. The magnitude of increase in nitro-JAK2 was attenuated in animals treated with vitamin E prior to LPS. The increase in nitro-JAK2 after LPS was greater in a line of experimental animals with a genetic propensity for higher PR at the given LPS dose than responses measured in their normal counterparts. The development and remission of nitro-JAK2 was temporally concordant with changes in plasma concentrations of IGF-I; hepatocellular IGF-I mRNA content was inversely proportional to nitro-JAK2 content. Localized changes in the state of nitration of regulatory phosphorylation domains of JAK2 in caveolar microenvironments and tissue content of JAK2 during PR suggest a unique mechanism through which discrete signal transduction switching might occur in the liver to fine tune cellular responses to the endocrine-immune signals that develop during low-level, transient proinflammatory stress.

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