Loop diuretics affect skeletal myoblast differentiation and exercise-induced muscle hypertrophy.

Muscle wasting or sarcopenia contributes to morbidity and mortality in patients with cancer, renal failure, or heart failure, and in elderly individuals. Na+-K+-2Cl- cotransporter 1 (NKCC1) is highly expressed in mammalian skeletal muscle, where it contributes to the generation of membrane ion currents and potential. However, the physiologic function of NKCC1 in myogenesis is unclear. We investigated this issue using the NKCC1 inhibitors bumetanide and furosemide, which are commonly used loop diuretics. NKCC1 protein levels increased during C2C12 murine skeletal myoblast differentiation, similarly to those of the myogenic markers myogenin and myosin heavy chain (MHC). NKCC1 inhibitors markedly suppressed myoblast fusion into myotubes and the expression of myogenin and MHC. Furthermore, phosphorylated and total NKCC1 levels were elevated in mouse skeletal muscles after 6 weeks' voluntary wheel running. Immunofluorescence analyses of myofiber cross-sections revealed more large myofibers after exercise, but this was impaired by daily intraperitoneal bumetanide injections (0.2 or 10 mg/kg/day). NKCC1 plays an essential role in myogenesis and exercise-induced skeletal muscle hypertrophy, and sarcopenia in patients with renal or heart failure may be attributable to treatment with loop diuretics.

Amino acids exhibit anti-inflammatory effects in human monocytic leukemia cell line, THP-1 cells.

OBJECTIVE: The elemental diet is one of the effective therapies for inflammatory bowel disease. However, the mechanism remains unclear, and there have never been reports about the inhibitory effects of amino acids in human monocytes/macrophages. We investigated the inhibitory effects of amino acids on cytokine production or expression of adhesion molecules that are involved in inflammatory diseases, in human monocytes/macrophages. METHODS: We examined the inhibitory effects of cysteine, histidine or glycine on the induction of nuclear factor-κB (NF-κB) activation, expression of intracellular adhesion molecule-1 (ICAM-1, CD54) and production of interleukin-8 (IL-8) in THP-1 cells, a human monocytic leukemia cell line, and peripheral blood mononuclear cells (PBMCs) stimulated with tumor necrosis factor-α (TNF-α). RESULTS: Cysteine, histidine and glycine significantly reduced the activation of NF-κB in THP-1 cells stimulated with TNF-α. In addition, cysteine and histidine significantly inhibited the expression of ICAM-1 and production of IL-8 in THP-1 cells and PBMCs. CONCLUSIONS: Our results suggest that cysteine and histidine exhibit anti-inflammatory effects in THP-1 cells, and may be responsible for the efficacy of treatment in inflammatory bowel diseases.

Matrix metalloproteinase haplotypes associated with coronary artery aneurysm formation in patients with Kawasaki disease.

Aneurysms of the vascular wall represent a final common pathway for a number of inflammatory processes, including atherosclerosis and idiopathic vasculitis syndromes. Kawasaki disease (KD) is an acute, self-limited vasculitis in children and the leading cause of acquired coronary artery aneurysms. We sought to identify shared molecular mechanisms of aneurysm formation by genotyping eight polymorphisms in matrix metalloproteinase (MMP)-1, 3, 7, 12 and 13 in the gene cluster on Chr.11q22, whose gene products have been implicated in aneurysm formation or are known to have elastase activity. We genotyped 482 US-UK KD patients (aneurysm+: n=111, aneurysm-: n=371) and tested our findings in an independent cohort of 200 Japanese KD patients (aneurysm+: n=58, aneurysm-: n=142). Analysis of the five MMP genes identified modest trends in allele and genotype frequencies for MMP-3 rs3025058 (-/T) and haplotypes containing MMP-3 rs3025058 (-/T) and MMP-12 rs2276109 (A/G) (nominal P=2 to 4 × 10(-5)) that conferred increased risk of aneurysm formation in US-UK subjects. This finding was validated in Japanese subjects and suggests the importance of this locus in aneurysm formation in children with KD. The region encompassing these risk haplotypes is a prime candidate for resequencing to look for rare genetic variation that may influence aneurysm formation.

Association of CCR2-CCR5 haplotypes and CCL3L1 copy number with Kawasaki Disease, coronary artery lesions, and IVIG responses in Japanese children.

BACKGROUND: The etiology of Kawasaki Disease (KD) is enigmatic, although an infectious cause is suspected. Polymorphisms in CC chemokine receptor 5 (CCR5) and/or its potent ligand CCL3L1 influence KD susceptibility in US, European and Korean populations. However, the influence of these variations on KD susceptibility, coronary artery lesions (CAL) and response to intravenous immunoglobulin (IVIG) in Japanese children, who have the highest incidence of KD, is unknown. METHODOLOGY/PRINCIPAL FINDINGS: We used unconditional logistic regression analyses to determine the associations of the copy number of the CCL3L1 gene-containing duplication and CCR2-CCR5 haplotypes in 133 Japanese KD cases [33 with CAL and 25 with resistance to IVIG] and 312 Japanese controls without a history of KD. We observed that the deviation from the population average of four CCL3L1 copies (i.e., four copies) was associated with an increased risk of KD and IVIG resistance (adjusted odds ratio (OR)=2.25, p=0.004 and OR=6.26, p=0.089, respectively). Heterozygosity for the CCR5 HHF*2 haplotype was associated with a reduced risk of both IVIG resistance (OR=0.21, p=0.026) and CAL development (OR=0.44, p=0.071). CONCLUSIONS/SIGNIFICANCE: The CCL3L1-CCR5 axis may play an important role in KD pathogenesis. In addition to clinical and laboratory parameters, genetic markers may also predict risk of CAL and resistance to IVIG.

Functional expression of cysteinyl leukotriene receptors on human platelets.

Normal peripheral blood leukocytes, such as basophils, eosinophils, B lymphocytes and monocytes/macrophages, have a cysteinyl leukotriene 1 (CysLT1) receptor, while the cysteinyl leukotriene 2 (CysLT2) receptor is expressed in cardiac Purkinje cells, endothelium, brain and leukocytes. However, it is unknown whether or not platelets express the CysLT1 or CysLT2 receptor. In this study we identify and characterize the biological function of the CysLT receptor of human platelets. We determined the CysLT1 or CysLT2 receptor mRNA expression in normal human platelets by RT-PCR and determined protein expression by Western blotting and flow cytometry. Moreover, we examined the effect of cysteinyl leukotrienes (CysLTs) in platelets on the induction of RANTES (Regulated on Activation, Normal T Expressed, and presumably Secreted). We also investigated whether the CysLT1 receptor antagonist pranlukast inhibits CysLT-induced RANTES release. In conclusion, we showed the functional expression of CysLT receptors on human platelets and demonstrated that CysLTs induced the release of significant amounts of RANTES, which suggests a novel role for human platelets in CysLT-mediated allergic inflammation.

Prostaglandin E2 suppresses beta1-integrin expression via E-prostanoid receptor in human monocytes/macrophages.

Beta1-integrins mediate cell attachment to different extracellular matrix proteins, intracellular proteins, and intercellular adhesions. Recently, it has been reported that prostaglandin E2 (PGE2) has anti-inflammatory properties such as inhibition of the expression of adhesion molecules or production of chemokines. However, the effect of PGE2 on the expression of beta1-integrin remains unknown. In this study, we investigated the effects of PGE2 on the expression of beta1-integrin in the human monocytic cell line THP-1 and in CD14+ monocytes/macrophages in human peripheral blood. For this, we examined the role of four subtypes of PGE2 receptors and E-prostanoid (EP) receptors on PGE2-mediated inhibition. We found that PGE2 significantly inhibited the expression of beta1-integrin, mainly through EP4 receptors in THP-1 cells and CD14+ monocytes/macrophages in human peripheral blood. We suggest that PGE2 has anti-inflammatory effects, leading to the inhibited expression of beta1-integrin in human monocytes/macrophages, and that the EP4 receptor may play an important role in PGE2-mediated inhibition.

Serum matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 levels in non-herpetic acute limbic encephalitis.

The pathogenesis of non-herpetic acute limbic encephalitis (NHALE) has been not clear. Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) play important roles in the function of the blood-brain barrier. We measured the serum concentrations of MMP-9 and TIMP-1 by using enzyme-linked immunosorbent assay (ELISA) in 23 patients with NHALE in the acute and convalescent stages. Serum MMP-9 concentrations and ratios of serum MMP-9/TIMP-1 were significantly higher (1) in patients with NHALE in acute and convalescent stages than in control patients (all P < 0.001); (2) in patients with NHALE at the acute stage compared with those at the convalescent stage (P = 0.004, and P = 0.014, respectively). In contrast, serum TIMP-1 concentrations were significantly lower in patients with NHALE in the acute and convalescent stages than in control patients (both P < 0.001) but did not differ in patients with NHALE in the acute and convalescent stages. Our preliminary study suggests that the prolonged imbalance of MMP-9 and TIMP-1 is associated with the pathogenesis of NHALE.

Clinical characteristics of respiratory syncytial virus infection-associated acute otitis media.

BACKGROUND: It is known that children with respiratory syncytial virus (RSV) infection frequently have complications of acute otitis media (AOM). METHODS: The hospital records of 148 inpatients aged 6-35 months who had RSV infection between January 2004 and December 2007, were retrospectively investigated. RESULTS: Forty-six out of 148 children (31%) had AOM. There was a significantly greater number of children with fever who had AOM (P = 0.005). The percentage of children with beta-lactamase-non-producing ampicillin-resistant (BLNAR) Haemophilus influenzae in nasopharyngeal culture who had AOM showed a tendency to be greater than that of those who did not have AOM, but this was not statistically significant (P = 0.068). Moreover, BLNAR H. influenzae was positive in middle ear fluid specimens from four of five children with AOM who underwent tympanocentesis. There were no significant differences in the incidence of lower airway infection, leukocytes counts, or serum C-reactive protein levels between children with and without AOM. CONCLUSIONS: Children who had RSV infection with AOM had a higher incidence of fever than those without AOM.

Characteristics of asthma attack with long-term management for bronchial asthma.

BACKGROUND: There have been no reports on the evaluation of the usefulness of long-term asthma management based on the Japanese Pediatric Guideline for the Treatment and Management of Bronchial Asthma 2005 (JPGL 2005). METHODS: The purpose of the present study was to retrospectively investigate the records of 350 patients admitted to Yamaguchi University Hospital who had asthma attacks from January 2006 to June 2008. There were 149 patients who were treated for more than 3 months in accordance with the guideline (long-term management group) and 201 who were not (non-long-term management group). The patients were divided into three age groups: 100 infants, 159 toddlers, and 91 schoolchildren. RESULTS: The onset age of asthma in the long-term management group was earlier than that in the non-long-term management group in toddlers and schoolchildren. The white blood cell counts and C-reactive protein levels were higher in the non-long-term management group in schoolchildren, suggesting the complication of some infections. The severity of asthma in the long-term management group was greater than that in the non-long-term management group among all three age groups. There were no significant differences, however, in the severity of asthma attack at admission between the long-term and non-long-term management groups in the three age groups. CONCLUSION: Patients who had severe asthma tended to be treated with long-term management, which suggests that long-term asthma management according to JPGL 2005 may reduce the severity of asthma attack at that admission, because the severity of asthma in patients undergoing long-term management correlates with the severity of asthma attack.

Different effects of novel mtDNA G3242A and G3244A base changes adjacent to a common A3243G mutation in patients with mitochondrial disorders.

Two novel mitochondrial DNA base changes were identified at both sides of the 3243A>G mutation, the most common mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). One was a 3244G>A transition in a girl with MELAS. The other was a 3242G>A transition in a girl with a mitochondrial disorder without a MELAS phenotype. Although the two base changes were adjacent to the 3243A>G mutation, they had different effects on the clinical phenotype, muscle pathology, and respiratory chain enzyme activity. Investigations of the different effects of the 3244G>A and 3242G>A base changes may provide a better understanding of tRNA dysfunction in mitochondrial disorders.

The effect of inhaled corticosteroids on Chlamydophila pneumoniae and Mycoplasma pneumoniae infection in children with bronchial asthma.

The purpose of this study was to clarify whether inhaled corticosteroids (ICSs) increased the infectious load of Chlamydophila pneumoniae and/or Mycoplasma pneumoniae in the respiratory tracts of asthmatic children. We studied a total of 310 outpatients with chronic stable asthma. Real-time polymerase chain reaction (PCR)-positive results for C. pneumoniae were obtained in 21 of 310 (6.8%) throat samples and 21 of 293 (7.2%) nasopharyngeal samples. There was no significant difference in the rate of detection or in the quantity of detection for C. pneumoniae between the ICS group and the non-ICS group, nor were there differences among groups classified by Japanese pediatric guidelines (JPGL) severity criteria. Real-time PCR-positive results for M. pneumoniae were obtained in 60 of 310 (19.4%) throat samples and 49 of 293 (16.7%) nasopharyngeal samples. There was no significant difference in the rate of detection or the quantity of detection between the ICS group and the non-ICS group, nor were there differences among age groups. The results of this research do not support the hypothesis that ICSs influence the infectious load of C. pneumoniae and M. pneumoniae. ICSs did not increase C. pneumoniae or M. pneumoniae infection in the upper respiratory tract, in contrast to the effect of ICSs in causing oral candidiasis. Our data exclude the concern that there is an increase in C. pneumoniae and M. pneumoniae infections due to ICS use, the use of ICSs being the gold standard in the long-term anti-inflammatory treatment of persistent asthma in children and adults.

Cysteinyl leukotrienes induce monocyte chemoattractant protein-1 in human monocyte/macrophages via mitogen-activated protein kinase and nuclear factor-kappaB pathways.

BACKGROUND: We have previously demonstrated that cysteinyl leukotriene (CysLT) induced monocyte chemoattractant protein-1 (MCP-1) production in monocytes/macrophages. The intracellular signal transduction pathway of MCP-1 production induced by CysLT in human monocytes/macrophages is unclear. METHODS: The activation of mitogen-activated protein kinase (MAPK), including extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 MAPK by phosphorylation, and nuclear factor-kappaB (NF-kappaB) by leukotriene (LT) D(4) and LTC(4) was determined in THP-1 cells, a human monocytic leukemia cell line, and peripheral blood CD14+ monocytes/macrophages. We examined the inhibitory effects of inhibitors of ERK1/2, JNK, p38 MAPK and NF-kappaB and pranlukast as a CysLT1 receptor antagonist on induction of MCP-1 production by LTD(4) and LTC(4). RESULTS: LTD(4) and LTC(4) induced significant phosphorylations of ERK1/2 and JNK, but not p38 MAPK, in THP-1 cells and peripheral blood CD14+ monocytes/macrophages. Pretreatment with the ERK1/2 inhibitor PD98059 and JNK inhibitor SP600125 attenuated MCP-1 production by CysLTs. NF-kappaB activation was induced by addition of LTD(4) and LTC(4). Pretreatment with the NF-kappaB inhibitors caffeic acid phenylethyl ester and MG-132 inhibited MCP-1 production by CysLTs. Pranlukast inhibited phosphorylation of ERK1/2 and JNK, NF-kappaB activation, and the MCP-1 production induced by CysLTs. CONCLUSION: CysLTs induce MCP-1 and this induction is mediated by ERK1/2 and JNK in MAPK, and NF-kappaB pathways via the CysLT1 receptor, for the most part, in human monocytes/macrophages.

MMP-9 and TIMP-1 in the cord blood of premature infants developing BPD.

We investigated matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) levels in the cord blood of 29 premature infants who were <30 weeks gestation. One, 8, and 14 infants developed severe, moderate and mild bronchopulmonary dysplasia (BPD), respectively, and 6 did not. MMP-9 and TIMP-1 levels in the cord blood were determined by ELISA. MMP-9/TIMP-1 ratios in the cord blood of infants who developed severe or moderate BPD (n = 9) were significantly higher than those who developed mild BPD or did not develop BPD (n = 20; P = 0.015). Multivariate linear regressions demonstrated that MMP-9 levels and MMP-9/TIMP-1 ratios in the cord blood of the premature infants correlated with the oxygen supplementation period (r = 0.58, P = 0.003 and r = 0.41, P = 0.030, respectively). The MMP-9 levels and MMP-9/TIMP-1 ratios correlated with the severity of maternal chorioamnionitis (both trend P = 0.006). The MMP-9 levels and MMP-9/TIMP-1 ratios in the cord blood may be related to the pathogenesis and severity of BPD and maternal chorioamnionitis.

Serial cerebrospinal fluid neurofilament concentrations in bacterial meningitis.

Neurofilament (NF) is one of the major cytoskeleton proteins of neurons. We investigated the concentrations of the heavy subunit of NF (NF-H) in cerebrospinal fluid (CSF) as biomarkers of neuronal injury in bacterial meningitis. Concentrations of NF-H in CSF of 26 children with bacterial meningitis and in 16 control subjects were measured by ELISA. The CSF NF-H levels were elevated in 22 of the 26 children (85%) with bacterial meningitis. The peak CSF NF-H level occurred at a median period of 10.5 days after onset of illness (range, 1 to 35 days). The peak CSF NF-H levels of the patients with neurological sequelae (n=4) were significantly higher than those without sequelae (n=22) (7.06 vs. 2.46 ng/mL as median, p=0.048). There was no significant difference in CSF NF-H levels between patients with and without severe neurological sequelae up to day 14 of illness, but the CSF NF-H levels in patients with sequelae were significantly higher than in those without sequelae after day 14 of illness (2.04 vs. 1.19 ng/mL as median, p=0.024). We suggest that neuronal injury occurs in bacterial meningitis regardless of the presence or absence of neurological sequelae.

Clinical characteristics of benign convulsions with rotavirus gastroenteritis.

Convulsions sometimes occur in infants and toddlers with mild gastroenteritis. We retrospectively investigated the hospital records of 106 patients admitted to our hospital who had rotavirus gastroenteritis from February 2002 to April 2008. There were 23 patients with convulsions, including 13 with benign convulsions, 9 with febrile seizures, and 1 with epilepsy. Gastroenteritis in patients with benign convulsions was mild from the viewpoint of body weights and serum creatinine concentrations on admission and the duration of admission. Serum Na(+) and Cl(-) concentrations of patients with benign convulsions were relatively lower than those without convulsions on admission (P = .006, and P = .008, respectively). Twelve of thirteen patients had no other seizures after oral administration of 5 mg/kg of carbamazepine, while 1 patient had 1 convulsion 15 minutes after the therapy. In conclusion, carbamazepine therapy was effective for benign convulsions with rotavirus gastroenteritis.

Anti-inflammatory effect of 1alpha,25-dihydroxyvitamin D(3) in human coronary arterial endothelial cells: Implication for the treatment of Kawasaki disease.

Kawasaki disease (KD) is an acute febrile vasculitis in childhood that is associated with inflammatory cytokines, in which the vascular inflammation results in damage to the coronary arteries. The active form of vitamin D, 1alpha,25-dihydroxyvitamin D(3) {1alpha,25-(OH)(2)D(3)} exhibits anti-inflammatory activities. In this study, we determined the mRNA and protein expression of the vitamin D receptor in human coronary arterial endothelial cells (HCAEC) by RT-PCR and Western blotting, respectively. We examined whether or not 1alpha,25-(OH)(2)D(3) inhibits the tumor necrosis factor-alpha (TNF-alpha)-induced activation of nuclear transcription factor-kappaB (NF-kappaB), which is essential for the expression of proinflammatory cytokines in HCAEC, by ELISA. In addition, we determined the inhibitory effect of 1alpha,25-(OH)(2)D(3) on E-selectin expression induced by TNF-alpha in HCAEC by flow cytometry. RT-PCR revealed mRNA for the vitamin D receptor in HCAEC. Western blotting demonstrated vitamin D receptor protein in HCAEC. ELISA showed that pretreatment with 1alpha,25-(OH)(2)D(3) significantly inhibited the TNF-alpha-induced NF-kappaB activation in HCAEC. Moreover, flow cytometry revealed that pretreatment with 1alpha,25-(OH)(2)D(3) significantly inhibited the TNF-alpha-induced expression of E-selectin on HCAEC. Our results suggest that adjunctive 1alpha,25-(OH)(2)D(3) may modulate the inflammatory response during KD vasculitis.

Serum and cerebrospinal fluid levels of cytokines in acute encephalopathy associated with human herpesvirus-6 infection.

Human herpesvirus-6 (HHV-6) is a causative agent of exanthema subitum. The immunological pathogenesis of acute encephalopathy associated with HHV-6 infection is still unclear. We measured the concentrations of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, IL-10, and soluble TNF receptor 1 (sTNFR1) in serum and cerebrospinal fluid (CSF) during the acute stage in 15 infants with acute encephalopathy and 12 with febrile seizures associated with HHV-6 infection. The serum IL-6, IL-10, sTNFR1, CSF IL-6, and sTNFR1 levels of infants with encephalopathy who had neurological sequelae (n=9) were significantly higher than those with febrile seizures (p=0.011, 0.043, 0.002, 0.029, and 0.005, respectively). In acute encephalopathy, serum IL-6, sTNFR1, and CSF IL-6 levels in infants with neurological sequelae were significantly higher than those without (n=6) neurological sequelae (p=0.043, 0.026, and 0.029, respectively), and serum IFN-gamma, IL-6, IL-10, and sTNFR1 levels were significantly higher than those in the CSF (p=0.037, 0.037, 0.001, and 0.021, respectively). There were no significant differences in serum or CSF cytokine levels between infants who were positive for HHV-6 DNA in the CSF (n=6) compared to those who were negative (n=9). We suggest that cytokines mediate the pathogenesis of acute encephalopathy associated with HHV-6 infection, and that the elevated levels of serum IL-6, sTNFR1, and CSF IL-6 are important for predicting neurological sequelae.

Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in perinatal asphyxia.

Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) play important roles in the function of the blood-brain-barrier (BBB). We investigated the roles of MMP-9 and TIMP-1 in the pathogenesis of hypoxic-ischemic encephalopathy following perinatal asphyxia. Serum concentrations of MMP-9 and TIMP-1 were determined by ELISA in 12 neonates with perinatal asphyxia and 15 controls on the birth day and the next day. Serum MMP-9 concentrations in asphyxiated neonates with neurological sequelae (n=5) were significantly higher than concentration in asphyxiated neonates without sequelae (n=7) and controls on birth day (p=0.003 and p<0.001, respectively). The ratios of serum MMP-9/TIMP-1 on birth day in asphyxiated neonates with neurological sequelae were significantly higher than those in asphyxiated neonates without sequelae (p=0.048). There were no significant differences in the serum MMP-9 concentrations or the ratios of MMP-9/TIMP-1 between asphyxiated neonates with and without neurological sequelae on the day after birth. Our preliminary study suggests that serum MMP-9 levels on birth day are important for predicting neurological prognosis of neonates with asphyxia.

Cysteinyl leukotrienes induce macrophage inflammatory protein-1 in human monocytes/macrophages.

BACKGROUND: Macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta are known for their chemotactic and proinflammatory effects on monocytes/macrophages which have a cysteinyl leukotriene 1 (CysLT(1)) receptor. METHODS: We examined MIP-1alpha and MIP-1beta production stimulated by CysLTs (LTC(4), LTD(4), and LTE(4)) in THP-1 cells, a human monocytic leukemia cell line, and peripheral blood mononuclear cells (PBMCs). Moreover, we examined the inhibitory effect of pranlukast, a CysLT(1) receptor antagonist, and inhibitors of three major mitogen-activated protein kinases (MAPK) on the induction of MIP-1alpha and MIP-1beta production by CysLTs. RESULTS: ELISA demonstrated that CysLTs induced MIP-1alpha and MIP-1beta production in THP-1 cells and PBMCs. PCR demonstrated that LTD(4) increased MIP-1alpha and MIP-1beta mRNA expressions in THP-1 cells. Pranlukast blocked MIP-1alpha and MIP-1beta production promoted by LTD(4) in THP-1 cells and PBMCs. Moreover, an inhibitor of extracellular signal-regulated kinase (ERK) attenuated the induction of MIP-1alpha and MIP-1beta production by LTD(4) in THP-1 cells whereas the inhibitors of c-Jun NH2-terminal kinase or p38 MAPK did not. CONCLUSION: CysLTs induce MIP-1alpha and MIP-1beta production mediated by ERK via binding to the CysLT(1) receptor in human monocytes/macrophages.

Mononuclear cell subpopulations in CSF and blood of children with bacterial meningitis.

OBJECTIVES: To elucidate mononuclear cell subsets of the cerebrospinal fluid (CSF) in order to investigate the pathogenesis of bacterial meningitis (BM). METHODS: Mononuclear cell and lymphocyte subsets in CSF and peripheral blood from 10 children with acute-stage BM before treatment on the same day were measured by flow cytometry. The control subjects for the subsets of peripheral blood were 15 healthy children. RESULTS: The percentages of CD14+ monocytes/macrophages (median: 56.5%), activated CD14+CD16+ monocytes/macrophages (20.9%), and CD14+CD16+ cells among total CD14+ cells (37.9%) in the CSF were significantly higher than those in the blood of children with BM (p<0.01, p<0.01, and p<0.05, respectively), which were significantly higher than those of the controls (p<0.001, p<0.001, p<0.05, respectively). The percentages of CD3+ (77.3%), CD4+ (45.2%), and CD8+ T cells (32.6%) in the CSF were significantly higher than those in the blood of affected children (p<0.01, p<0.01, and p<0.05, respectively). The percentages of CD3+, CD4+, and CD8+ T cells in the blood of children with BM were significantly lower than those of controls (all p<0.001). The percentages of CD20+ B cells (6.9%) in the CSF were significantly lower than those in the blood of affected children (p<0.01), which were significantly higher than those of controls (p<0.001). CONCLUSION: The percentages of monocytes/macrophages and T cells in CSF were higher than those in blood in children with BM.