Abstract
IL-16 is an immunomodulatory cytokine that is characterized by chemotactic activity and stimulation of proinflammatory cytokine expression in monocytic cells. We studied IL-16 using ELISA in children with meningitis. When meningeal symptoms existed, IL-16 levels were high in the cerebrospinal fluid (CSF) of both bacterial (939 ± 877 ng/l, n = 20) and aseptic (341 ± 371 ng/l, n = 23) meningitis. The values in the CSF were significantly higher than those in non-meningitis controls (29 ± 8 ng/l, n = 22, P < 0·0001). After meningeal symptoms disappeared, IL-16 levels in bacterial (191 ± 149 ng/l, n = 10, P = 0·0042) and aseptic (159 ± 188 ng/l, n = 13, P = 0·0118) meningitis were lower than those during the symptomatic stage. IL-16 levels were the highest before day 5 of the illness and then gradually fell. Significant correlations were found between IL-16 levels and both G-CSF levels (r = 0·783, n = 11, p = 0·0029) and IL-6 levels (r = 0·818, n = 12, P = 0·0005) in the CSF of bacterial and aseptic meningitis. IL-16 levels in all CSF samples from non-meningitis controls were lower than those in serum. In contrast, IL-16 levels in the CSF in six of 16 samples from bacterial meningitis and two of 18 samples from aseptic meningitis were higher than those in serum. Serum levels of IL-16 did not fluctuate throughout the course of meningitis. These data indicate that IL-16 levels rise transiently in CSF at the initial stage of meningitis. We speculate that IL-16 may promote inflammatory responses during meningitis in concert with other proinflammatory cytokines.
Keywords: cerebrospinal fluid, children, IL-16, meningitis
Introduction
Interleukin-16 (IL-16), an immunomodulatory cytokine, was described as the first T cell chemoattractant factor generated from mitogen- or antigen-stimulated peripheral blood mononuclear cells [1,2]. IL-16 is synthesized by T cells, eosinophils, dendritic cells, fibroblasts, epithelial cells and neuronal cells [3]. Caspase-3 enzymatically cleaves pro-IL-16 to a mature form of IL-16, which is biologically active as a multimer [3–6]. Mature IL-16 exerts CD4-dependent and -independent effects [1,3]. Mature IL-16 has a variety of biological activities: (i) migration of CD4+ T cells, eosinophils, monocytes and dendritic cells [3,7,8]; (ii) cell cycle progression of T cells [3,9]; (iii) adhesion molecule (α4α7) expression on eosinophils [3]; (iv) induction of early gene phosphorylation [10]; (v) HLA-DR expression on monocytes [3]; and (vi) pro-B cell differentiation [11]. Additionally, IL-16 can stimulate the synthesis of proinflammatory cytokines, including IL-1β, IL-6 and tumour necrosis factor (TNF)-α in monocytic cells [12]. This cytokine may play a role in various inflammatory diseases, such as allergic asthma [13,14], rheumatoid arthritis [15], systemic lupus erythematosus [16] and acquired immunodeficiency syndrome [17,18]. Thus, IL-16 is postulated to be a proinflammatory and immunoregulatory molecule, playing an important role in recruitment and activation of immune cells at the site of inflammation.
A variety of cytokines, such as TNF-α, IL-1, IL- 6, IL-8, IL-12, granulocyte-cerebrospinal fluid (G-CSF) and macrophage inflammatory protein (MIP)-1α play critical roles in local inflammatory responses in the CSF in meningitis [19–23]. Elevated levels of these inflammatory cytokines are found in the CSF at the initial stage of meningitis. Anti-inflammatory cytokines, such as IL-10 [24] and transforming growth factor (TGF)-β [25], mitigate the inflammatory process by inhibiting the production of inflammatory cytokines. These stimulatory and inhibitory cytokines make cytokine networks during the inflammatory process in bacterial and aseptic meningitis [25]. IL-16 was reported by Lahrtz et al. [26] to be detected in the CSF in one-third of cases with aseptic meningitis. However, little is known about how the IL-16 levels in the CSF change during meningitis. In this study, we show that IL-16 levels are increased transiently at the initial stage of bacterial and aseptic meningitis in children.
Subjects and methods
Study subjects
We studied 13 patients with bacterial meningitis, 23 patients with aseptic meningitis and 22 controls without meningitis (Table 1). The patients with meningitis fitted the following criteria: (i) fever, headache, vomiting and stiff neck; (ii) cell counts>35/µl in the CSF; and (iii) in bacteriological studies, bacteria isolated from the CSF in bacterial meningitis, and sterile CSF in aseptic meningitis. The bacterial meningitis pathogens included Group B streptococcus in five patients, Streptococcus pneumoniae in three, Haemophilus influenzae in three, Escherichia coli in one and Listeria in one. The aseptic meningitis pathogens included the mumps virus in five, echovirus 9 in one, echovirus 30 in one, coxsackie virus A4 in one, coxsackie virus B4 in one and undetectable causes in 14 individuals. The symptomatic stage was designated as the period when any of the meningeal symptoms or signs existed, and the recovery stage as the period after all the symptoms and signs disappeared. The first day of the illness was determined as the day when all the meningitis symptoms first occurred. The controls without meningitis fit the following criteria: (i) cell counts <5/µl in the CSF; (ii) CSF negative in bacteriological and viral studies. They consisted of six with febrile convulsions, eight with epilepsy, four with headaches and four with fever, vomiting and headaches. We obtained blood samples from 25 disease-free controls who came for routine examination before minor elective surgery or for a health examination, according to the criteria used previously [27,28].
Table 1.
Clinical characteristics of the study subjects
| Bacterial meningitis | Aseptic meningitis | ||||
|---|---|---|---|---|---|
| Symptomatic stage | Recovery stage | Symptomatic stage | Recovery stage | Non-meningitis controls | |
| Patient no. (M/F) | 13 (8/5)1·9 ± 2·2 | 23 (18/5)5·4 ± 3·8 | 22 (15/7) | ||
| Age (years) | 1·9 ± 2·2 | 5·4 ± 3·8 | 5·9 ± 3·8 | ||
| CSF | |||||
| Total cells (106/l) | 5241 ± 13 291 | 316 ± 708 | 312 ± 321 | 36 ± 60 | 2 ± 2 |
| MNC (106/l) | 391 ± 432 | 204 ± 406 | 246 ± 308 | 33 ± 57 | 1 ± 1 |
| Neutrophils (106/l) | 2012 ± 2158 | 112 ± 306 | 66 ± 134 | 3 ± 5 | 1 ± 2 |
| Glucose (mmol/l) | 3·7 ± 3·3 | 3·8 ± 1·7 | 5·7 ± 1·1 | 4·6 ± 1·1 | 7·4 ± 2·5 |
| Protein (g/l) | 1·94 ± 2·63 | 0·85 ± 0·83 | 0·33 ± 0·27 | 0·31 ± 0·21 | 0·19 ± 0·13 |
| Blood | |||||
| Leukocytes (109/l) | 13·6 ± 8·1 | 7·2 ± 4·3 | 9·4 ± 4·1 | 7·3 ± 2·2 | 7·8 ± 3·2 |
| Neutrophils (109/l) | 9·9 ± 7·6 | 3·6 ± 4·0 | 6·5 ± 4·3 | 2·5 ± 0·93 | 5·4 ± 3·2 |
| CRP (mg/l) | 11·9 ± 10·3 | 2·1 ± 5·3 | 2·3 ± 6·2 | 0·1 ± 0·1 | 1·2 ± 4·3 |
| Body temperature (°C) | 38·6 ± 1·2 | 37·7 ± 0·6 | 38·7 ± 0·9 | 37·1 ± 0·3 | 38·2 ± 0·9 |
Data are expressed as the means ± s.d. MNC, mononuclear cells; CRP, C-reactive protein; ND, not done.
Sample collection
We obtained institutional approval from the responsible committee and full consent from each of the patient's parents for this study. To minimize the patient's risk throughout this study, lumbar punctures were performed only when indicated clinically, as shown previously [24]. The control children received lumbar punctures to rule out meningitis. The CSF samples were immediately centrifuged at 150 g for 10 min, and the supernatant was stored at − 30°C. Serum specimens were collected at the same time and stored at − 30°C.
Enzyme-linked immunosorbent assay (ELISA) to measure cytokines
IL-16 concentrations were measured in duplicate by an ELISA (Endogen, Woburn, MA, USA). Briefly, 50 µl of CSF and serum or standard recombinant human IL-16 were dispensed into 96-well plates precoated with an anti-IL-16 antibody. IL-16 was then sandwiched with a biotinylated antibody against human IL-16. After that, horseradish peroxidase-conjugated streptavidin, a substrate solution and a stop solution were added sequentially. This ELISA system specifically recognized human IL-16, and its measuring range was 25–2000 ng/l. G-CSF values were assessed by a chemiluminescent enzyme immunoassay and the minimal detectable concentration of this cytokine was 1 ng/l (Chugai Pharmaceutical, Tokyo, Japan) [28]. Concentrations of IL-6 were quantified by an ELISA (Toray-Fuji Bionics, Tokyo, Japan) and the minimal detectable concentrations were 25 ng/l.
Statistical analysis
Results are expressed as means ± s.d. unless stated otherwise. Probability of a significant difference was determined using the Mann–Whitney U-test. Relationships between IL-16 levels and other indices were assessed using Pearson's correlation coefficients. Differences were considered significant when the two-tailed P-value was <0·05.
Results
High IL-16 levels in the CSF of meningitis patients
IL-16 levels in the CSF of meningitis patients and non-meningitis controls are shown in Table 2. When meningeal symptoms were present, IL-16 levels in the CSF of both bacterial (939 ± 877 ng/l) and aseptic (341 ± 371 ng/l) meningitis were significantly higher than those in nonmeningitis controls (29 ± 8 ng/l, P < 0·0001). The IL-16 levels in bacterial meningitis were higher than those of aseptic meningitis (P = 0·0085). After meningeal symptoms disappeared, IL-16 levels in the CSF of bacterial (191 ± 149 ng/l) and aseptic (159 ± 188 ng/l) meningitis were lower than those during the corresponding symptomatic stage (P = 0·0042 and P = 0·0118). The IL-16 levels during the recovery stage were not significantly different between bacterial and aseptic meningitis. Figure 1 illustrates the kinetics of IL-16 levels in the CSF of bacterial (Fig. 1a) and aseptic (Fig. 1b) meningitis. In 21 of 22 corresponding individuals examined longitudinally, IL-16 levels were the highest during the first 5 days of illness and then fell gradually.
Table 2.
IL-16 levels in the cerebrospinal fluid (CSF) and serum
| Bacterial meningitis | Aseptic meningitis | ||||
|---|---|---|---|---|---|
| Symptomatic stage | Recovery stage | Symptomatic stage | Recovery stage | Non-meningitis controls | |
| CSF (ng/l) | 939 ± 877 (n = 20)*† | 191 ± 149 (n = 10) | 341 ± 371 (n = 23)‡ | 159 ± 188 (n = 13) | 29 ± 8 (n = 22)§ |
| Serum (ng/l) | 1399 ± 1075 (n = 12) | 1195 ± 838 (n = 8) | 1802 ± 1102 (n = 15) | 1626 ± 1267 (n = 9) | 2219 ± 1131 (n = 10) |
Data are expressed as the means ± s.d. ND, not done.
CSF: P = 0·0085 versus at symptomatic stage of aseptic meningitis,
P = 0·0042 versus recovery stage of bacterial meningitis;
P = 0·0118 versus at recovery stage of aseptic meningitis;
P < 0·0001 versus symptomatic and recovery stages of both bacterial and aseptic meningitis.
Fig. 1.
Kinetics of IL-16 levels in the cerebrospinal fluid of individuals with bacterial (a) and aseptic (b) meningitis. Filled symbols, symptomatic stage; open symbols, period without meningeal symptoms.
Relationships between IL-16 levels and clinical indices
Figure 2 shows significant correlations between IL-16 levels and both levels of G-CSF (r = 0·783, P = 0·0029) and IL-6 (r = 0·818, P = 0·0005) in the CSF of bacterial and aseptic meningitis. Correlations were not significant in the CSF of bacterial meningitis between IL-16 levels and both counts of leucocytes (r = 0·276, n = 28) and mononuclear cells (r = 0·030, n = 27). In aseptic meningitis, however, a significant relationship in the CSF samples collected simultaneously was found between IL-16 levels and both counts of leucocytes (r = 0·470, P = 0·0045, n = 34) and mononuclear cells (r = 0·547, P = 0·0006, n = 34). IL-16 levels in the CSF were not correlated significantly with clinical features such as the grade or duration of fever, headache or vomiting, or the concentrations of glucose or protein in the CSF.
Fig. 2.
Relationships among IL-16 levels and both granulocyte colony-stimulating factor (G-CSF) and IL-6 levels in the cerebrospinal fluid of patients with bacterial and aseptic meningitis. Filled symbols, bacterial meningitis; open symbols, aseptic meningitis; circles, symptomatic stage; triangles, period without meningeal symptoms; solid line, linear regression line.
Serum IL-16 levels
IL-16 was detected in all serum samples in meningitis and nonmeningitis controls. IL-16 levels were not significantly different among these groups (Table 2). The mean serum levels in both bacterial and aseptic meningitis were similar in the symptomatic and recovery stages. The serum IL-16 levels in bacterial and aseptic meningitis during the symptomatic stage and non-meningitis controls were significantly higher than those in disease-free controls (800 ± 776 ng/l, n = 25) (P = 0·0497, P = 0·0020 and P = 0·0012, respectively). The IL-16 levels during the recovery stage were not significantly different from those in disease-free controls. In paired samples collected simultaneously from CSF and serum, IL-16 levels in all CSF samples from non-meningitis controls were lower than those in serum (Fig. 3). In contrast, IL-16 levels in the CSF in six of 16 samples from bacterial meningitis and two of 18 samples from aseptic meningitis were higher than those in serum.
Fig. 3.
Comparison of IL-16 levels between the cerebrospinal fluid (CSF) and serum of individuals with bacterial meningitis, aseptic meningitis, and non-meningeal controls. Paired samples were collected simultaneously from CSF and serum. Circles, symptomatic stage; triangles, period without meningeal symptoms.
Discussion
New information has emerged from our study regarding the kinetics of IL-16 levels in the CSF during meningitis. Our study revealed that IL-16 levels in the CSF were high during the symptomatic stage of bacterial and aseptic meningitis. The cytokine values were the highest during the first 5 days of illness and then dropped, with an improvement of meningeal signs or symptoms. This increase in IL-16 levels in the CSF was more prominent in bacterial meningitis than that in aseptic meningitis. These data indicate that IL-16 levels rise transiently in the CSF at the initial stage of bacterial and aseptic meningitis.
When IL-16 levels were compared between samples simultaneously collected from the CSF and serum in our study, the levels in all CSF samples from nonmeningitis controls were lower than those in serum. Indeed, IL-16 levels in the CSF in six of 16 samples from bacterial meningitis and two of 18 samples from aseptic meningitis were higher than those in serum. IL-16 levels in the CSF rose in the initial stage of meningitis, but serum levels did not fluctuate throughout the course of the illness. These results suggest that the high levels of IL-16 in the CSF are not likely to come from IL-16 in blood that crossed the blood–brain barrier. In fact, our data showed a significant correlation between IL-16 levels and mononuclear cell counts in the CSF of patients with aseptic meningitis. These results suggest that IL-16 can be produced, at least in part, intrathecally.
IL-16 is generated as pro-IL-16 in T cells [3–6]. Caspase-3 enzymatically cleaves pro-IL-16 to a mature IL-16 after stimulation of T cells [3–6]. IL-16 mRNA was expressed constitutively in T cells; the mRNA levels did not correlate with IL-16 protein synthesis [3,6]. The expression of caspase-3 is induced in vitro by inflammatory stimuli, such as lipopolysaccharides, IFN-α, IFN-γ and viruses [29–32]. Thus, bioactive IL-16 secretion is regulated by caspase-3 activation after stimulation of T cells. As for bacterial meningitis, active caspase-3 was detected in the hippocampus in patients who underwent autopsy [33]. Active caspase-3-positive neurones were observed in rabbits after intracisternal infection with S. pneumoniae [33]. Our preliminary studies showed caspase-3 in CSF cells collected during meningitis by ELISA and Western blotting (data not shown). A variety of cells, such as T cells, dendritic cells, fibroblasts, epithelial cells, microglial cells and neuronal cells can produce IL-16 [3,34]. The cellular source of IL-16 in the central nervous system (CNS) during meningitis remains unknown. This cytokine was expressed by infiltrating immune cells such as lymphocytes and microglial cells in cerebral infarctions [34]. These cells might release IL-16 during meningitis. Taken together, we believe that IL-16 could be produced via caspase-3 activation in the CNS during meningitis.
IL-16 acts as a chemoattractant for migration of CD4+ T cells and monocytes [3, 4, 7, 8, 9]. In the CSF during meningitis, lymphocytes and monocytes are dominant after the initial stage, although neutrophils accumulate initially [25]. This accumulation of neutrophils is perhaps because of increased levels of IL-1, IL-8, G-CSF, TNF-α, and MIP-1α [19–23]. Our present study showed a significant correlation between IL-16 levels and both counts of leucocytes and mononuclear cells in the CSF of patients with aseptic meningitis. These data suggest that IL-16 contributes to the migration of these mononuclear cells into the CSF. Additionally, IL-16 may be a chemoattractant for dendritic cells in human CSF, because the numbers of plasmacytoid and myeloid dendritic cells increase under several neuroinflammatory conditions [3, 4, 7, 8, 9,35]. IL-16 could orchestrate the interaction of helper T cells, monocytes and dendritic cells during the induction phase of an immune response [7].
IL-16 can stimulate the synthesis of proinflammatory cytokines, including IL-1β, IL-6 and TNF-α in monocytic cells [12]. These cytokines are thought to be produced at lower levels in aseptic meningitis than in bacterial meningitis [36,37]. This may be due to the lower IL-16 concentrations found in the CSF of aseptic meningitis patients. Additionally, we found significant relationships between IL-16 levels and both levels of G-CSF and IL-6 in the CSF. Our previous reports showed elevated levels of G-CSF and IL-6 in the CSF in the initial stage of meningitis [20,21]. We speculate that IL-16 expression may contribute to the inflammatory responses during meningitis in concert with other proinflammatory cytokines.
Acknowledgments
We thank Mr Hiroyuki Abe for excellent technical assistance and Drs Yasufumi Ozawa and Fumio Morohashi for important clinical suggestions.
References
- 1.Center DM, Cruikshank W. Modulation of lymphocyte migration by human lymphokines. I. Identification and characterization of chemoattractant activity for lymphocytes from mitogen-stimulated mononuclear cells. J Immunol. 1982;128:2563–8. [PubMed] [Google Scholar]
- 2.Cruikshank W, Center DM. Modulation of lymphocyte migration by human lymphokines. II. Purification of a lymphotactic factor (LCF) J Immunol. 1982;128:2569–74. [PubMed] [Google Scholar]
- 3.Cruikshank WW, Kornfeld H, Center DM. Interleukin-16. J Leukoc Biol. 2000;67:757–66. doi: 10.1002/jlb.67.6.757. [DOI] [PubMed] [Google Scholar]
- 4.Zhang Y, Center DM, Cruikshank WW, et al. Processing and activation of pro-interleukin-16 by caspase-3. J Biol Chem. 1998;273:1144–9. doi: 10.1074/jbc.273.2.1144. [DOI] [PubMed] [Google Scholar]
- 5.Baier M, Bannert N, Werner A, Lang K, Kurth R. Molecular cloning, sequence, expression, and processing of the interleukin 16 precursor. Immunology. 1997;94:5273–7. doi: 10.1073/pnas.94.10.5273. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Sciaky D, Brazer W, Center DM, Cruikshank WW, Smith TJ. Cultured human fibroblasts express constitutive IL-16 mRNA. cytokine induction of active IL-16 protein synthesis through a caspase-3-dependent mechanism. J Immunol. 2000;164:3806–14. doi: 10.4049/jimmunol.164.7.3806. [DOI] [PubMed] [Google Scholar]
- 7.Kaser A, Dunzendorfer S, Offner FA, et al. B lymphocyte-derived IL-16 attracts dendritic cells and Th cells. J Immunol. 2000;165:2474–80. doi: 10.4049/jimmunol.165.5.2474. [DOI] [PubMed] [Google Scholar]
- 8.Kaser A, Dunzendorfer S, Offner FA, et al. A role for IL-16 in the cross-talk between dendritic cells and T cells. J Immunol. 1999;163:3232–8. [PubMed] [Google Scholar]
- 9.Nicoll J, Cruikshank WW, Brazer W, Liu Y, Center DM, Kornfeld H. Identification of domains in IL-16 critical for biological activity. J Immunol. 1999;163:1827–32. [PubMed] [Google Scholar]
- 10.Cruikshank WW, Berman JS, Theodore AC, Bernado J, Center DM. Lymphokine activation of T4+ lymphocytes and monocytes. J Immunol. 1987;138:3817–23. [PubMed] [Google Scholar]
- 11.Szabo P, Kesheng Z, Kirman I, et al. Maturation of B cell precursors is impaired in thymic-deprived nude and old mice. J Immunol. 1998;161:2248–53. [PubMed] [Google Scholar]
- 12.Mathy NL, Bannert N, Norley SG, Kurth R. Cutting edge: CD4 is not required for the functional activity of IL-16. J Immunol. 2000;164:4429–32. doi: 10.4049/jimmunol.164.9.4429. [DOI] [PubMed] [Google Scholar]
- 13.Hessel EM, Cruikshank WW, Van Ark I, et al. Involvement of IL-16 in the induction of airway hyper-responsiveness and up-regulation of IgE in a murine model of allergic asthma. J Immunol. 1998;160:2998–3005. [PubMed] [Google Scholar]
- 14.Laberge S, Ernst P, Ghaffar O, et al. Increased expression of interleukin-16 in bronchial mucosa of subjects with atopic asthma. Am J Respir Cell Mol Biol. 1997;17:193–202. doi: 10.1165/ajrcmb.17.2.2750. [DOI] [PubMed] [Google Scholar]
- 15.Klimiuk PA, Goronzy JJ, Weyand CM. IL-16 as an anti-inflammatory cytokine in rheumatoid synovitis. J Immunol. 1999;162:4293–9. [PubMed] [Google Scholar]
- 16.Lee S, Kaneko H, Sekigawa I, Tokano Y, Takasaki Y, Hashimoto H. Circulating interleukin-16 in systemic lupus erythematosus. Br J Rheumatol. 1998;37:1334–7. doi: 10.1093/rheumatology/37.12.1334. [DOI] [PubMed] [Google Scholar]
- 17.Truong MJ, Darcissac ECA, Hermann E, Dewulf J, Capron A, Bahr GM. Interleukin-16 inhibits human immunodeficiency virus type 1 entry and replication in macrophages and in dendritic cells. J Virol. 1999;73:7008–13. doi: 10.1128/jvi.73.8.7008-7013.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Zhou P, Devadas K, Tewari D, Jegorow A, Notkins AL. Processing, secretion, and anti-HIV-1 activity of IL-16 with or without a signal peptide in CD4+ T cells. J Immunol. 1999;163:906–12. [PubMed] [Google Scholar]
- 19.Benveniste EN. Inflammatory cytokines within the central nervous system: sources, function, mechanism of action. Am J Physiol. 1992;263:C1–C16. doi: 10.1152/ajpcell.1992.263.1.C1. [DOI] [PubMed] [Google Scholar]
- 20.Fukushima K, Ishiguro A, Nakamura T, et al. Elevated levels of interleukin 6 in the cerebrospinal fluid in childhood aseptic meningitis. Jpn J Inflam. 1993;13:263–8. [Google Scholar]
- 21.Fukushima K, Ishiguro A, Shimbo T. Transient elevation of granulocyte colony-stimulating factor levels in cerebrospinal fluid at the initial stage of aseptic meningitis in children. Pediatr Res. 1995;37:160–4. doi: 10.1203/00006450-199502000-00006. [DOI] [PubMed] [Google Scholar]
- 22.Inaba Y, Ishiguro A, Shimbo T. The production of macrophage inflammatory protein-1α in the cerebrospinal fluid at the initial stage of meningitis of children. Pediatr Res. 1997;42:788–93. doi: 10.1203/00006450-199712000-00012. [DOI] [PubMed] [Google Scholar]
- 23.Ishiguro A, Suzuki Y, Inaba Y, et al. The production of IL-8 in cerebrospinal fluid in aseptic meningitis of children. Clin Exp Immunol. 1997;109:426–30. doi: 10.1046/j.1365-2249.1997.4681366.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Ishiguro A, Suzuki Y, Inaba Y, Komiyama A, Koeffler HP, Shimbo T. Production of interleukin-10 in the cerebrospinal fluid in aseptic meningitis of children. Pediatr Res. 1996;40:610–4. doi: 10.1203/00006450-199610000-00016. [DOI] [PubMed] [Google Scholar]
- 25.Van Furth AM, Roord JJ, Van Furth R. Roles of proinflammatory and anti-inflammatory cytokines in pathophysiology of bacterial meningitis and effect of adjunctive therapy. Infect Immun. 1996;64:4883–90. doi: 10.1128/iai.64.12.4883-4890.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Lahrtz F, Piali L, Nadal D, et al. Chemotactic activity on mononuclear cells in the cerebrospinal fluid of patients with viral meningitis is mediated by interferon-γ inducible protein-10 and monocyte chemotactic protein- Eur J Immunol. 1997;27:2484–9. doi: 10.1002/eji.1830271004. [DOI] [PubMed] [Google Scholar]
- 27.Ishiguro A, Nakahata T, Matsubara K, et al. Age-related changes in thrombopoietin in children: reference interval for serum thrombopoietin levels. Br J Haematol. 1999;106:884–8. doi: 10.1046/j.1365-2141.1999.01641.x. [DOI] [PubMed] [Google Scholar]
- 28.Ishiguro A, Inoue K, Nakahata T, et al. Reference intervals for serum granulocyte colony-stimulating factor levels in children. J Pediatr. 1996;128:208–12. doi: 10.1016/s0022-3476(96)70391-8. [DOI] [PubMed] [Google Scholar]
- 29.Ludwiczek O, Kaser A, Koch RO, Vogel W, Cruikshank WW, Tilg H. Activation of caspase-3 by interferon α causes interleukin-16 secretion but fails to modulate activation induced cell death. Eur Cytokine Netw. 2001;12:478–86. [PubMed] [Google Scholar]
- 30.Ochiai TK, Fukushima K, Ochiai K. Lipopolysaccharide stimulates butyric-acid-induced apoptosis in human peripheral blood mononuclear cells. Infect Immun. 1999;67:22–9. doi: 10.1128/iai.67.1.22-29.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Pirhonen J, Sareneva T, Julkunen I, Matikainen S. Virus infection induce proteolytic processing of IL-18 in human macrophages via caspase-1 and caspase-3 activation. Eur J Immunol. 2001;31:726–33. doi: 10.1002/1521-4141(200103)31:3<726::aid-immu726>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
- 32.Dai C, Krantz SB. Interferon ã induces upregulation and activation of caspases 1, 3, and 8 to produce apoptosis in human erythroid progenitor cells. Blood. 1999;93:3309–16. [PubMed] [Google Scholar]
- 33.Gerber J, Brück W, Stadelmann C, Bunkowski S, Lassmann H, Nau R. Expression of death-related proteins in dentate granule cells in human bacterial meningitis. Brain Pathol. 2001;11:422–31. doi: 10.1111/j.1750-3639.2001.tb00410.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Schwab JM, Nguyen TD, Meyermann R, Schluesener HJ. Human focal cerebral infarctions induce differential lesional interleukin-16 (IL-16) expression confined to infiltrating granulocytes, CD8+ T-lymphocytes and activated microglia/macrophages. J Neuroimmunol. 2001;114:232–41. doi: 10.1016/s0165-5728(00)00433-1. [DOI] [PubMed] [Google Scholar]
- 35.Pashenkov M, Huang YM, Kostulas V, Haglund M, Söderström M, Link H. Two subsets of dendritic cells are present in human cerebrospinal fluid. Brain. 2001;124:480–92. doi: 10.1093/brain/124.3.480. [DOI] [PubMed] [Google Scholar]
- 36.Tang RB, Lee BH, Chung RL, Chen SJ, Wong TT. Interleukin-1beta and tumor necrosis factor-alpha in cerebrospinal fluid of children with bacterial meningitis. Childs Nerv Syst. 2001;17:453–6. doi: 10.1007/s003810000422. [DOI] [PubMed] [Google Scholar]
- 37.Dulkerian SJ, Kilpatrick L, Costarino AT, Jr, et al. Cytokine elevations in infants with bacterial and aseptic meningitis. J Pediatr. 1995;126:872–6. doi: 10.1016/s0022-3476(95)70199-0. [DOI] [PubMed] [Google Scholar]