Life threatening proinflammatory response (PR) induces severe GH resistance. Though 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 JAK2. Employing a low-level, in vivo endotoxin (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) co-immunoprecipitated with caveolin-1 and ₁₁₇₇phospho-SER-endothelial nitric oxide synthase when post-LPS liver homogenates were treated with anti-caveolin-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-1; hepatocellular IGF-1 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 in 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.