P65 Subunit Of Nuclear factor-kappaB Research Articles

Lipopolysaccharide Induces Type 2 Iodothyronine Deiodinase in the Mediobasal Hypothalamus: Implications for the Nonthyroidal Illness Syndrome

To determine whether the type 2 iodothyronine deiodinase (D2), the principal central nervous system enzyme converting T(4) to biologically active T(3), is regulated in tanycytes by immune activation, D2 activity was measured in the mediobasal hypothalamus (MBH) 4, 12, and 24 h after administration of bacterial lipopolysaccharide (LPS) and compared with D2 levels in the cortex and anterior pituitary of rats. In contrast to D2 activity in the cortex and anterior pituitary that showed a steady linear increase over 24 h, which was coincident with a decline in thyroid hormone and TSH levels, D2 activity peaked in the MBH 12 h after LPS administration. By in situ hybridization, the increased D2 mRNA synthesis induced by LPS was specifically localized to tanycytes lining the third ventricle. In vitro assays in HC11 and HEK-293 cells demonstrated that the p65 subunit of nuclear factor-kappaB markedly increased both rat and human D2 genes (dio2) as analyzed by promoter assays. No activation of human dio2 was observed when an 83-bp minimal promoter was used. We propose that LPS or LPS-induced cytokines directly induce D2 mRNA in tanycytes. The ensuing MBH-specific D2-mediated local thyrotoxicosis may suppress the hypothalamus-pituitary-thyroid axis by local feedback inhibition of hypophysiotropic TRH and/or TSH and contribute to the mechanism of central hypothyroidism associated with infection.

Diesel exhaust particles enhance lung injury related to bacterial endotoxin through expression of proinflammatory cytokines, chemokines, and intercellular adhesion molecule-1.

Epidemiologic studies demonstrate acute and serious adverse effects of particulate air pollution on respiratory health, especially in people who are susceptible to bacterial infection. However, the underlying mechanism remains to be elucidated. To provide experimental evidence for the epidemiologic data, we determined the effects of diesel exhaust particles (DEP), major participants in particulate pollutants, on lung injury related to bacterial endotoxin in mice. Intratracheal instillation of DEPs synergistically enhanced lung injury related to endotoxin from gram-negative bacteria, which was characterized by neutrophil sequestration, interstitial edema, and alveolar hemorrhage. In the presence of endotoxin, DEPs further activated the nuclear translocation of p65 subunit of nuclear factor-kappaB (NF-kappaB) in the lung and increased the lung expression of intercellular adhesion molecule-1, interleukin-1beta, macrophage chemoattractant protein-1, keratinocyte chemoattractant (KC), macrophage inflammatory protein-1alpha, and Toll-like receptors. DEPs given alone increased the lung expression of Toll-like receptor 4 and the nuclear localization of p50 subunit of NF-kappaB. The combined exposure to DEPs and endotoxin decreased nuclear localization of CCAAT/enhancer binding protein beta. These results provide the first experimental evidence that DEPs enhance neutrophilic lung inflammation related to bacterial endotoxin. The enhancement is mediated by the induction of proinflammatory molecules, likely through the expression of Toll-like receptors and the activation of p65-containing dimer(s) of NF-kappaB, such as p65/p50.

X-Linked Vacuolated Myopathy: TNF-α and IFN-γ Expression in Muscle Fibers with MHC Class I on Sarcolemma

The presence and the distribution of tumor necrosis factor-alpha, interferon-gamma, and p65 subunit of nuclear factor-kappaB, molecules known to induce synergistically and to mediate major histocompatibility complex (MHC) class I expression, were determined in muscle sections from control and X-linked vacuolated myopathy patients. MHC class I colocalized with tumor necrosis factor-alpha and interferon-gamma, as well as with p65, in most of the membrane attack complex- and/or calcium-positive muscle fibers in X-linked vacuolated myopathy. These results suggest that the expression of MHC class I in X-linked vacuolated myopathy could be induced by tumor necrosis factor-alpha and interferon-gamma and partly mediated by nuclear factor-kappaB.