. Effects of protein malnutrition on IL-6-mediated signaling in the liver and the systemic acute-phase response in rats. Am J Physiol Regul Integr Comp Physiol 287: R801-R808, 2004; 10.1152/ajpregu.00715.2003.-This study examines the effects of malnutrition on IL-6 signaling pathways of rats fed 2% vs. 20% casein diets for 14 days. Effects of malnutrition on the abundance and IL-6-stimulated phosphorylation of signaling proteins in the JAK-STAT and MAP kinase pathways were examined in the liver. Changes of the acute-phase response as reflected by serum ␣1-acid glycoprotein (AG), TNF-␣ (TNF), and IL-1 (IL-1) were compared in the two dietary groups at 0, 4, 8, 16, and 24 h after IL-6 administration. Under basal conditions, the abundance of the IL-6 receptor, gp130, JAK1, STAT1, and STAT3 proteins and levels of phosphorylation of ERK1/2 and p38 were significantly increased in the liver in the 2% casein group compared with the 20% casein group. With IL-6 stimulation, the increased phosphorylation per unit of protein of these signaling proteins was not different in the liver between the two groups. Before IL-6 stimulation, serum levels of TNF, IL-1, IL-6, and AG were significantly higher in the 2% casein group than in the 20% casein group. After bolus injection of IL-6, changes in IL-1 and AG were similar in the two dietary groups, although a slight decline in AG level was noted after 8 h of IL-6 administration in the 2% protein group. These data demonstrate that protein malnutrition produces changes in inflammation-related proteins characteristic of a low-grade systemic inflammatory response and, thus, can serve as an inflammatory stimulus. The capacity for response to IL-6 is preserved, suggesting adaptive preservation of acute-phase responsiveness during malnutrition.
Posthemorrhagic hydrocephalus (PHHC) represents a major complication of preterm birth. The aim of this study was to determine whether cerebrospinal fluid (CSF) levels of the proinflammatory cytokines IL-1, IL-18, and interferon (IFN)-␥ are altered in the CSF of preterm infants with PHHC and may serve as a marker of white matter damage (WMD). Twenty-seven preterm infants with PHHC were included in the study; 13 of them had signs of cystic WMD (cWMD) on ultrasound examinations. CSF sample 1 was obtained at first ventriculostomy, sample 2 at shunt implantation. Results were compared with a control group of 20 age-matched patients without neurologic diseases. IL-1 concentrations were elevated in CSF sample 1 of PHHC patients without WMD and in sample 1 of patients with cWMD. Concentrations of IL-18 were increased in both samples of patients without WMD and in sample 2 of patients with cWMD. CSF levels of IFN-␥ were elevated in sample 1 of PHHC patients with cWMD. The pro-inflammatory cytokine IL-1 and IL-18 levels in the CSF are elevated in patients with PHHC. Higher IFN-␥ levels are detected in a subgroup of patients developing cWMD, indicating its involvement in the pathogenesis of cWMD in the context of PHHC. H ydrocephalus following IVH represents a major complication of preterm birth and may result in adverse neurologic outcome in later life. IVH is associated with damage to the white matter, which is exacerbated by hydrocephalus (1). Pressure, distortion, ischemia, and inflammation seem to contribute to this process (2). Although shunting CSF is often an effective treatment, it may prevent only some of the neurologic changes. The identification of mechanisms, mediators, and markers of hydrocephalus appears critical to improve the treatment and prevention of neurologic disability caused by hydrocephalus and associated WMD.It is now widely accepted that immune and inflammatory processes take place in the brain in response to diverse insults such as infection, neurodegenerative disorders, trauma, hemorrhage, and hypoxia-ischemia (3-5). Brain inflammation is characterized by infiltration of circulating immune cells and by activation of resident cells, including microglia. These cells can express, release, and respond to inflammatory mediators. In the CNS, one of the most widely studied is the proinflammatory cytokine IL-1. In the immature brain, caspase-1, which is responsible for cleavage of the proinflammatory cytokines IL-1 and IL-18 into their biologically active forms, seems to be an important mediator of brain injury (6). There is extensive evidence of direct involvement of IL-1 in adult and also in developmental brain injury (7-11). The next member of the IL-1 family, previously designated "IFN-␥ inducing factor," has many properties similar to IL-1. To date, only few studies have addressed the function of IL-18 in the context of injury to the immature CNS. Data from animal experiments indicate that IL-18 has an influence on the development of WMD in the immature brain (12). IL-18 itself ma...
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