ABSTRACT
BACKGROUND: beta-Adrenergic receptor stimulation appears to have contrasting effects on inflammatory processes. METHODS: In 25 healthy volunteers we examined the effects of a 20-min isoproterenol infusion (20 ng/kg/min) on systemic and peripheral blood mononuclear cell (PBMC) production of LPS-stimulated inflammatory mediators. RESULTS: Plasma soluble CD40 ligand and stimulated MIP-1alpha production were both reduced (p < or = 0.05) by systemic beta-adrenergic stimulation. Stimulated TNF-alpha production was reduced (p < 0.03) but plasma TNF-alpha was unchanged. In contrast, plasma IL-6 was elevated (p < 0.05) while stimulated IL-6 was unchanged, indicating the main source may not be PBMCs. CONCLUSIONS: beta-Adrenergic receptor activation leads to a reduction in markers of the early inflammation cascade. Our findings also suggest that adipose tissue is a contributing source of beta-adrenergically stimulated increases in circulating IL-6. Since beta-adrenergic agonists and antagonists are commonly used in the treatment of disease, it is important that we clearly elucidate and contrast their systemic versus cell-specific effects.
Subject(s)
Adrenergic beta-Agonists/pharmacology , CD40 Ligand/drug effects , Chemokine CCL3/drug effects , Inflammation/drug therapy , Leukocytes, Mononuclear/drug effects , Receptors, Adrenergic, beta/drug effects , Adipose Tissue/drug effects , Adipose Tissue/immunology , Adipose Tissue/metabolism , Adult , Biomarkers/analysis , Biomarkers/blood , CD40 Ligand/blood , CD40 Ligand/immunology , Chemokine CCL3/immunology , Chemokine CCL3/metabolism , Down-Regulation/drug effects , Down-Regulation/physiology , Female , Humans , Inflammation/blood , Inflammation/immunology , Interleukin-6/blood , Isoproterenol/pharmacology , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides , Male , Middle Aged , Neuroimmunomodulation/drug effects , Neuroimmunomodulation/immunology , Receptors, Adrenergic, beta/metabolism , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/drug effectsABSTRACT
Hypoxia is defined as a deficiency of oxygen reaching the tissues of the body, and it plays a critical role in development and pathological conditions, such as cancer. Once tumors outgrow their blood supply, their central portion becomes hypoxic and the tumor stimulates angiogenesis through the activation of the hypoxia-inducible factors (HIFs). HIFs are transcription factors that are regulated in an oxygen-dependent manner by a group of prolyl hydroxylases (known as PHDs or HPHs). Our understanding of hypoxia signaling is limited by our incomplete knowledge of HIF target genes. cDNA microarrays and a cell line lacking a principal HIF protein, HIF1alpha, were used to identify a more complete set of hypoxia-regulated genes. The microarrays identified a group of 286 clones that were significantly influenced by hypoxia and 54 of these were coordinately regulated by cobalt chloride. The expression profile of HIF1alpha -/- cells also identified a group of downregulated genes encoding enzymes involved in protecting cells from oxidative stress, offering an explanation for the increased sensitivity of HIF1alpha -/- cells to agents that promote this type of response. The microarray studies confirmed the hypoxia-induced expression of the HIF regulating prolyl hydroxylase, PHD2. An analysis of the members of the PHD family revealed that they are differentially regulated by cobalt chloride and hypoxia. These results suggest that HIF1alpha is the predominant isoform in fibroblasts and that it regulates a wide battery of genes critical for normal cellular function and survival under various stresses.
