Caveolae nitration of Janus kinase-2 at the 1007Y-1008Y site: coordinating inflammatory response and metabolic hormone readjustment within the somatotropic axis.
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 (1007)Y-(1008)Y phosphorylation epitope of JAK2, we demonstrated that the nitrated (1007)Y-(1008)Y-JAK-2 (nitro-JAK2) coimmunoprecipitated with caveolin-1 and (1177)phospho-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.
Elsasser
Ted H
TH
Growth Biology Laboratory, US Department of Agriculture, Agricultural Research Service, Beltsville, Maryland 20705, USA. elsasser@anri.barc.usda.gov
Kahl
Stanislaw
S
Li
Cong-Jun
CJ
Sartin
James L
JL
Garrett
Wesley M
WM
Rodrigo
José
J
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D001224:Aspartic Acid / Q000378:metabolism; D001665:Binding Sites; D002417:Cattle; D021941:Caveolae / Q000201:enzymology* / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D053614:Janus Kinase 2 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008969:Molecular Sequence Data; D009566:Nitrates / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D013312:Stress, Physiological / Q000276:immunology / Q000378:metabolism*; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D014810:Vitamin E / Q000378:metabolism / Q000494:pharmacology
D000906:Antibodies; D000975:Antioxidants; D000939:Epitopes; D008070:Lipopolysaccharides; D009566:Nitrates; D012333:RNA, Messenger; D050826:Suppressor of Cytokine Signaling Proteins; D014810:Vitamin E; D001224:Aspartic Acid; D018698:Glutamic Acid; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D052250:Nitric Oxide Synthase Type III; D053614:Janus Kinase 2