Divergent effects of LPS on expression of IL-1 receptor family members in mononuclear phagocytes in vitro and in vivo

Three molecules, interleukin 1 (IL-1) receptor I (IL-1RI), IL-1 receptor II (IL-1RII or decoy) and IL-1 receptor accessory protein (IL-1R AcP or IL-1RIII), are involved in IL-1 binding and signal transduction. In addition, three homologous genes (T1/ST2, MyD88 and rsc786) have been identified. Expression of the signal transducing type I R and of the decoy type II R in human monocytes is regulated by pro- and anti-inflammatory signals. The present study was designed to evaluate comprehensively how a prototypic pro-inflammatory signal, bacterial lipopolysaccharide (LPS), affects expression of IL-1R family members in mononuclear phagocytes in vitro and in vivo. Resting human monocytes expressed high levels of IL-1RII, IL-1R AcP, MyD88 and rsc786, whereas low levels of IL-1RI and T1/ST2 were present. In vitro exposure to LPS augmented expression of IL-1RI, T1/ST2 and MyD88, whereas it inhibited that of IL-1RII and rsc786. Expression of IL-1R AcP in monocytes was less substantially affected by LPS. The expression of IL-1R family members was also studied in organs of mice given LPS. As expected on the basis of in vitro results, organs (e.g. spleen, lungs and peritoneal exudate cells) from LPS-treated mice showed increased levels of IL-1RI, T1/ST2 and MyD88. Intriguingly, while expression of IL-1RII was inhibited in peritoneal macrophages after LPS, in accordance with in vitro results, increased IL-1RII mRNA was observed in organs such as liver, lungs and spleen. This unexpected effect of LPS was drastically reduced in mice rendered neutropenic by 5-fluorouracil. Therefore, we conclude that the apparent induction of IL-1RII in certain organs of LPS-treated mice is due to recruitment of myeloid cells which express high levels of decoy RII. Therefore, members of IL-1R family are independently and divergently regulated in mononuclear phagocytes exposed to the prototypic pro-inflammatory signal LPS in vitro and in vivo.     

HIV-1 gp120 modulates hypothalamic cytokine mRNAs in vivo: implications to cytokine feedback systems

HIV-1-derived envelope glycoprotein 120 (gp120) may play an important role in HIV-1 neuropathology. Gp120 may act through mediators including proinflammatory cytokines. Here, we investigated the regulation of the IL-1 beta system [IL-1 beta, IL-1 receptor type I (IL-1RI), IL-1 receptor antagonist (IL-1Ra), IL-1 receptor accessory proteins (IL-1R AcP I and II)], TNF-alpha, TGF-alpha, and TGF-beta 1 mRNAs in the hypothalamus of Wistar rats in response to the chronic intracerebroventricular (ICV) microinfusion (via osmotic minipumps) of HIV-1 gp120 (100, 500, and 1000 ng/24 h for 72 h). Gp120 increased IL-1 beta, IL-1Ra, TNF-alpha, and TGF-beta 1 mRNAs. Gp120-induced cytokine mRNA profiles were highly intercorrelated in the same samples. Levels of IL-1RI, IL-1R AcP I and II, and TGF-alpha did not change significantly, and levels of GAPDH mRNA were constant. The data suggest potential cytokine-cytokine interactions with positive (IL-1 beta<-->TNF-alpha) and negative (IL-1Ra-->IL-1 beta; TGF-beta 1-->IL-1 beta/TNF-alpha) feedback in gp120 action. A dysregulation of the balance between stimulatory and inhibitory cytokine mechanisms may participate in the initiation, propagation, and/or aggravation of HIV-1 neuropathology.     

Solution structure of synthetic peptide inhibitor and substrate of cAMP-dependent protein kinase. A study by 2D H NMR and molecular dynamics

Altered hepatic expression of apolipoproteins occurs during the acute phase response. Here we examined whether the acute phase response alters extra hepatic expression of apolipoproteins. Syrian hamsters were injected with endotoxin (LPS), tumor necrosis factor (TNF), interleukin (IL)-1, or the combination of TNF + IL-1 and mRNAs for serum amyloid A (apoSAA), apolipoprotein (apo) J, apo E. apo A-I, and apo D, were analyzed. LPS increased mRNA levels for apoSAA in all tissues examined. LPS and TNF + IL-1 increased mRNA levels for apo J in kidney, heart, stomach, intestine, and muscle. Individually, TNF and IL-1 were less potent than the combination of the two cytokines. LPS decreased mRNA levels for apo E in all tissues, except for mid and distal intestine. TNF and IL-1 were less effective than LPS. LPS, TNF + IL-1 and TNF decreased mRNA levels for apo A-I in duodenum. mRNA for apo D decreased in heart, were unchanged in brain and increased in muscle, following LPS. The widespread extra hepatic regulation of the apolipoproteins during the acute phase response may be important for the alterations in lipid metabolism that occur during infection and inflammation as well as the immune response.     

Clumsiness in children: a defect of kinaesthetic perception?

The distribution of type I interleukin-1 receptor (IL-1R1) mRNA in the rat brain was examined by in situ hybridization technique. IL-1R1 mRNA was expressed in several brain regions including the anterior olfactory nucleus, medial thalamic nucleus, posterior thalamic nucleus, basolateral amygdaloid nucleus, ventromedial hypothalamic nucleus, arcuate nucleus, median eminence, mesencephalic trigeminal nucleus, motor trigeminal nucleus, facial nucleus and Purkinje cells of the cerebellum. Furthermore, we identified neuronal expression of IL-1R1 mRNA using simultaneous detection (double in situ hybridization) of IL-1R1 mRNA with neuron specific enolase mRNA. In addition to the expression in neuronal cells, IL-1R1 mRNA was also expressed on the vascular walls and the epithelial cells of the choroid plexus and the ventricles. These findings suggest the possibility that IL-1 produces its multiple effects on the central nervous system through the actions not only on neuronal cells but also on endothelial and epithelial cells.     

What are we changing with neurocognitive rehabilitation? Illustrations from two single cases of changes in neuropsychological performance and brain systems as measured by SPECT

We investigated the effectiveness of lipopolysaccharide (LPS) and muramyl dipeptide (MDP) administered into the brain to induce anorexia in acutely fasted Wistar rats allowed to refeed. We also assayed for changes in mRNA levels of IL-1 system components, TNF-alpha, TGF-beta1, glycoprotein 130 (gp 130), leptin receptor (OB-R), pro-opiomelanocortin (POMC), neuropeptide Y (NPY), glucocorticoid receptor (GR), and CRF receptor (CRF-R) in selected brain regions. The data show that LPS and MDP induced anorexia differentially during refeeding. LPS-induced anorexia was of a stronger magnitude and duration than that of MDP. RNase protection assays showed that LPS and MDP significantly increased the expression of IL-1beta, IL-1 receptor type I, and TNF-alpha mRNAs in the cerebellum, hippocampus, and hypothalamus; LPS was more potent in all cases. MDP treatment, on the other hand, induced a stronger increase in hypothalamic levels of IL-1 receptor antagonist (IL-1Ra) and TGF-beta1 mRNAs relative to LPS. In addition, competitive RT-PCR analysis showed that LPS induced an eleven-fold increase in IL-1alpha mRNA in the hypothalamus relative to vehicle. These findings suggest that LPS and MDP mediate anorexia through different cytokine mechanisms. A stronger up-regulation of anti-inflammatory cytokines (IL-1Ra and TGF-beta1) mRNA expression by MDP may be involved in the weaker MDP-induced anorexia relative to LPS. No significant changes were observed in the peptide components examined except for an up-regulation in cerebellar gp 130 mRNA and down-regulation of hypothalamic GR mRNA expression in response to LPS or MDP. This study shows that LPS and MDP induce anorexia in fasted rats allowed to refeed, and suggests an important role for endogenous cytokine-cytokine interactions.     

An inter district quality partnership: the experience of a large rural health service

The interleukin-2 receptor (IL-2R) gamma chain (gamma c chain) is shared by IL-4R, IL-7R, IL-9R, and IL-15R and plays an important role in regulation of the immune system. However, its regulation in monocytic cell lines has not been well clarified. We examined the expression and regulation of the IL-2R alpha, IL-2R beta, gamma c chain, IL-4R and IL-7R mRNA in a human monoblastic leukemia cell line, THP-1. Unstimulated THP-1 cells constitutively expressed a low level of gamma c chain and IL-4R mRNA. Phorbol myristate acetate (PMA) induced macrophage-like differentiation and up-regulated the gamma c chain mRNA expression in THP-1 cells. This effect of PMA was suppressed by the protein kinase inhibitors H-7 and staurosporine. PMA did not affect the expression of the other IL-R mRNAs examined. 1 alpha, 25(OH)2D3 and interferon-gamma also induced differentiation of THP-1 cells, but these reagents did not affect the expression of the IL-R mRNAs in THP-1 cells. These findings suggest that the expression of the gamma c chain mRNA is regulated by the PMA-dependent pathway and is not associated with that of the other IL-R mRNAs.     

An immunohistochemical assessment of cathepsin D in gastric carcinoma: its impact on clinical prognosis

Immunohistochemical staining of normal and cancerous ovarian tissues has demonstrated that both IL-1 alpha and IL-1 beta are more strongly expressed in cancerous than in normal tissues and are secreted mainly by epithelial cells. We have shown by bioassay and immunoassay that cancerous, but not normal ovarian tissues constitutively secrete IL-1 in vitro. Activation of cancerous ovarian tissues by lipopolysaccharide (LPS) increased its capacity to secrete IL-1. Normal ovarian tissues secreted low amounts of IL-1 only after prolonged stimulation (72-96 h) by high doses of LPS (10-100 micrograms/ml). On the other hand, constitutive IL-1 was detected in homogenates of normal ovarian tissues and stimulation by LPS increased its capacity to produce IL-1. IL-1 beta was the main type of IL-1 secreted by cancerous ovarian tissues. IL-1 alpha was detected at lower levels. In contrast, in normal tissues similar amounts of both IL-1 alpha and IL-1 beta were detected in the supernatants. The levels of both types of IL-1, and also the bioactivity of IL-1 were significantly higher in cancerous than in normal ovarian tissues. Established primary cell lines from normal ovarian tissues did not secrete IL-1 into supernatants but did express it at very low levels. Stimulation with LPS did not affect the capacity of these cell lines to secrete IL-1 but it increased their capacity to express it. In contrast, primary established epithelial cell lines from cancerous ovarian tissues did secrete and express high levels of IL-1 and these levels were increased under stimulation with LPS. Cancerous ovarian tissues did not only secrete higher levels of both IL-1 alpha and beta than normal ovarian tissues, but also the mechanism controlling the secretion of these factors in cancerous ovarian tissues seemed to be different from that found in normal ovarian tissues. Our results suggest that paracrine/autocrine factors may be involved in the regulation of both types of IL-1 secreted by ovarian tissues. These cytokines may play a role in regulating the physiological, pathophysiological and oncogenic processes of the ovary.