Abstract
Objectives
Interleukin (IL)-33 is a cytokine with both pro- and anti-inflammatory effects involved in the pathogenesis of some inflammatory diseases. The purpose of this investigation was to evaluate the serum and cerebrospinal fluid (CSF) IL-33 concentrations in patients with multiple sclerosis (MS).
Methods
Blood specimens were obtained from 140 patients with MS (46 males and 94 females) with various disease patterns and treatment plans and 140 healthy subjects (47 males and 93 females), who acted as a control group. CSF samples were collected from 20 MS group and 20 sex- and age-matched patients with other neurological diseases of nonautoimmune etiology. The serum and CSF concentrations of IL-33 were measured by the enzyme-linked immunosorbent assay.
Results
The serum and CSF IL-33 levels were significantly higher in the MS group compared to the control group (p<0.001 and p<0.050, respectively). The serum IL-33 concentrations were also significantly higher in newly diagnosed (untreated) patients and patients treated with methylprednisolone or with interferon-β and methylprednisolone compared to the healthy patient group (p<0.007, p<0.002, and p<0.010, respectively). Moreover, the serum IL-33 concentrations in patients with relapsing-remitting (RRMS), primary progressive (PPMS), and secondary progressive (SPMS) forms of the disease were significantly higher than in the healthy control group (p<0.006, p<0.001, and p<0.020, respectively).
Conclusions
Our results showed increased concentrations of IL-33 in patients with MS including both untreated and treated MS patients and patients with the RRMS, SPMS, and PPMS forms. This suggests that IL-33 may be involved in the pathogenesis of all MS forms and treatment with methylprednisolone or both interferon-β plus methylprednisolone has no influence on IL-33 concentrations.
Keywords: Multiple Sclerosis; IL33 protein, human; Treatment
Introduction
Multiple sclerosis (MS) is an autoimmune-mediated demyelinating disease of the central nervous system (CNS). The disease has four clinical forms: relapsing-remitting (RRMS), progressive relapsing (PRMS), primary progressive (PPMS), and secondary progressive (SPMS).1
Autoreactive pathogenic helper T cells (Th) play a prominent role in the pathogenesis of MS. Experimental autoimmune encephalomyelitis (EAE) is the most frequently used animal model system for studying MS.2 Upon antigenic stimulation, naïve Th cells are activated and undergo several proliferations before finally differentiating into several subsets (i.e., Th1, Th2, Th17) and regulatory T cells (Treg), which are characterized by the production of particular cytokine profiles. Th1 cells that release inflammatory cytokines (e.g., interferon (IFN)-γ, tumor necrosis factor (TNF)-α) as well as Th17 cells that secrete interleukin (IL)-17 play central role in the pathogenesis of MS and EAE diseases.3 Treg cells, which secrete transforming growth factor (TFG)-β, and Th2 cells, which release IL-4, were thought to be important in diseases amelioration.4 Macrophages may also play a pivotal role in the pathogenesis of MS and EAE diseases.5 In our previous studies, higher levels of a Th17-related chemokine (CCL20) and lower levels of a Th2/Treg-related chemokine (CCL22) were observed in patients with MS.6,7
IL-33 is a new member of the IL-1 family. The IL-33 receptor is a heterodimer comprised of ST2L (or ST2) and IL-1R accessory protein (IL-1RAcP). ST2 is expressed on some leukocytes particularly on mast cells and activated Th2 cells. It acts to increase the effector function of these cells.8 The binding of IL-33 to its receptor induces the secretion of pro-inflammatory cytokines from mast cells and Th2 lymphocytes,8 stimulates the migration of Th2 cells,9 promotes the activation of the eosinophil, basophil, and natural killer (NK) cells,10 potentiates the Th1- and Th2-related immune responses,11 triggers IFN-γ secretion by invariant NK T cells (iNKT) and NK cells, and increases the count of iNKT cells in the spleen.12 The importance of IL-33 has been suggested in the strengthening of innate immunity and may act as an alarmin to activate the immune system following cell necrosis or apoptosis.13
IL-33 is a nuclear cytokine that constitutively expresses in endothelial and epithelial cells.13 Interestingly, the highest quantity of IL-33 expression in mice was found in the brain and spinal cord,14 suggesting the possible specific actions of IL-33 in the CNS additional to its role in the immune system. Recent investigations have also demonstrated that IL-33 may contribute to the pathogenesis of some inflammatory diseases suggesting that IL-33 may have strong pro-inflammatory characteristics.13,15 Although, there are a few studies regarding the association of IL-33 and MS, the influences of gender, MS patterns, and treatment program on IL-33 concentration have not been investigated. In this study, we sought to evaluate the concentration of IL-33 in MS patients and any association with gender, treatment programs, and disease patterns.
Methods
Peripheral blood specimens were collected from two groups between January 2013 and February 2014. Group one was comprised of 140 patients with MS (46 men and 94 women) who were referred to the Shephah Hospital of Kerman (a city in southeast Iran). MS was diagnosed by specialist neurologists, according to the McDonald’s criteria.16 Of the 140 patients, 102 patients presented with RRMS, 28 with SPMS, eight with PPMS, and two with PRMS. The patients were also differentiated as newly (n = 51) and previously diagnosed (n = 89). Newly diagnosed patients were enrolled into the study before receiving any treatment. Previously diagnosed patients were treated with methylprednisolone, IFN-β, or IFN-β plus methylprednisolone. The treated MS patients received intravenous methylprednisolone 1000 mg/day for three to five days following an acute MS attack or 30 μg intramuscular IFN-β once weekly (Avonex, Biogen, Massachusetts, US or CinnoVex, CinnoGen, Iran) or 44 μg subcutaneously, three times weekly (Rebif, Merck Serono, Switzerland) for at least three months. Some MS patients were initially treated with IFN-β (during the silent stage of disease) and after the occurrence of an acute MS attack with methylprednisolone.
Cerebrospinal fluid (CSF) samples were obtained from another 20 patients with MS (four men and 16 women) and 20 sex- and age-matched patients (five men and 15 women) with other neurological diseases of nonautoimmune etiology (such as a tension headache or meningitis). The CSF samples were obtained during routine diagnostic work-up or for other clinical purposes. CSF specimens were collected from patients who were not under immunosuppressive medication and were stored at –70 °C.
Group two (considered the control group) comprised of 140 healthy subjects (47 men and 93 women) that were recruited among blood donors of the Kerman Transfusion Organization. All control subjects were in basic good health, with no history of CNS disease or any other relevant disorders. Those with a history of recurrent infections, asthma, allergy, and atopic diseases, any suspected immunological disorders, malignancy, surgery, smoking, drug use, and major trauma within six months before blood sampling were all excluded from the study. A peripheral blood specimen was taken from all subjects, and the sera were separated and stored at –70 °C.
Our study was evaluated and approved by the Ethical Committee of Kerman University of Medical Sciences. All participants gave their written informed consent before enrollment.
The serum and CSF IL-33 concentrations were determined using commercial enzyme-linked immunosorbent assay (ELISA) kits (BosterBio, California, US) according to the manufacturer’s instruction. The sensitivity of the test was less than 10 pg/ml.
The Student’s t-test, analysis of variance (ANOVA), and chi-square tests were performed for comparison of variables between groups. The data were analyzed by SPSS Statistics (Chicago, Illinois, US) version 18. A p-value less than 0.050 was considered statistically significant.
Results
The mean age of patients with MS was 35.0±8.3 years and 36.1±8.1 years in the control group. There were 94 (67.1%) female patients with MS and 46 (32.9%) males. In the control group, there were 93 (66.4%) females and 47 (33.6%) males. There was no significant difference between the MS group and control group in age and gender distribution (p = 0.260 and p = 0.500, respectively).
CSF samples were obtained from 20 patients with MS and 20 age- and sex-matched control patients. The mean age was 33.6±9.3 years in the MS group and 35.3±7.0 years in the control group. There were 16 (80.0%) female and four (20.0%) male patients with MS and 15 (75.0%) female and five (20.0%) males in the control group. There was no significant difference between the patients with MS and the control group in mean age and gender distribution (p = 0.430 and p = 0.700, respectively).
The mean serum IL-33 concentration was 408.0±55.3 pg/ml in the MS group and 156.8±35.4 pg/ml in the control group. The serum IL-33 concentration was significantly higher in the MS group compared to the control group (p<0.001) [Table 1]. In the control group, the difference in the serum IL-33 concentrations between males and females was not significant. However, cytokine levels were found to be higher in females. In female MS patients, the serum IL-33 concentrations were significantly higher compared to male patients (p<0.050). In both male and female patients with MS, the serum IL-33 concentrations were significantly higher compared to patients in the control group of the same gender (p<0.050 and p<0.010, respectively) [Table 1].
Table 1. Serum levels of IL-33 in patients with MS patients and the control group according to gender.
| Group | Sex | Number | IL-33 levels* | p-value |
|---|---|---|---|---|
| MS | Male | 46 | 268.8±67.5 | 0.050 |
| Female | 94 | 492.2±77.6 | ||
| Total | 140 | 408.0±55.3 | ||
| Control | Male | 47 | 121.2±25.7 | 0.310 |
| Female | 93 | 192.3±65.9 | ||
| Total | 140 | 156.8±35.4 |
*Values expressed as mean±SD. The serum levels of cytokine are expressed as pg/ml. IL-33: interleukin-33; MS: multiple sclerosis; SD: standard deviation.
The mean CSF concentrations of IL-33 were 76.6±12.3 pg/ml in the MS group and 44.0±6.4 pg/ml in the control group. The CSF concentrations of IL-33 were significantly higher in the MS group than in the control group (p<0.050) [Table 2]. In the MS and control group, the difference in the mean CSF concentrations of IL-33 between men and women were not significant. In female patients with MS, the CSF concentrations of IL-33 were significantly higher compared to the control group (p<0.040). In males, this difference was not significant [Table 2].
Table 2. CSF levels of IL-33 in MS patients and control group according to gender.
| Group | Sex | Number | IL-33 levels* | p-value |
|---|---|---|---|---|
| MS | Male | 4 | 66.6±37.0 | 0.700 |
| Female | 16 | 79.1±13.0 | ||
| Total | 20 | 76.6±12.3 | ||
| Matched controls | Male | 5 | 38.4±7.3 | 0.500 |
| Female | 15 | 45.9±8.2 | ||
| Total | 20 | 44.1±6.4 |
*Values expressed as mean±SD. The CSF levels of cytokine expressed as pg/ml. CSF: cerebrospinal fluid; IL-33: interleukin-33; MS: multiple sclerosis; SD: standard deviation.
Serum IL-33 concentrations in newly diagnosed (untreated) and previously diagnosed (treated) MS patients are given in Table 3. Overall, the serum IL-33 concentrations in untreated and treated patients were significantly higher than the control group (p<0.007 and p<0.001, respectively). However, there was no significant difference between untreated and treated patients. In both untreated and treated patients, no significant differences were observed between males and females concerning the IL-33 concentrations [Table 3].
Table 3. Serum levels of IL-33 in newly (untreated) and previously diagnosed (treated) patients with MS according to gender.
| Group | Sex | Number | IL-33 levels* | p- value |
|---|---|---|---|---|
| Untreated | Male | 25 | 289.3±83.1 | 0.320 |
| Female | 26 | 452.4±140.9 | ||
| Total | 51 | 372.4±82.6 | ||
| Treated | Male | 21 | 244.4±112.1 | 0.100 |
| Female | 68 | 512.8±93.3 | ||
| Total | 89 | 433.4±628.9 | ||
| Control | Male | 47 | 121.2±25.7 | 0.310 |
| Female | 93 | 192.3±65.9 | ||
| Total | 140 | 156.7±35.4 |
*Values expressed as mean±SD. The serum levels of cytokine expressed as pg/ml. IL-33: interleukin-33; MS: multiple sclerosis; SD: standard deviation.
The serum IL-33 concentrations in treated MS patients with methylprednisolone or both of IFN-β plus methylprednisolone were significantly higher than the control group (p<0.002 and p<0.01, respectively). However, no significant difference was observed in patients treated with IFN-β and the control group. The serum IL-33 concentrations in patients treated with IFN-β was lower compared to untreated patients, but the difference was not significant [Table 4 and Table 5]. No significant differences were observed in the mean serum levels of IL-33 between patients treated with methylprednisolone, IFN-β, or both IFN-β plus methylprednisolone [Table 5].
Table 4. Serum levels of cytokine IL-33 in MS patients according to treatment.
| Group | Treatment | Number | IL-33 levels* | p-value |
|---|---|---|---|---|
| MS | IFN-β | 6 | 285.1±153.0 | 0.620 |
| MP | 16 | 511.8±187.6 | ||
| IFN-β+MP | 65 | 426.0±88.2 | ||
| No treatment | 51 | 372.5±82.6 | ||
| Control | - | 140 | 156.8±35.4 |
*Values expressed as mean±SD. The serum levels of cytokine expressed as pg/ml. IL-33: interleukin-33; MS: multiple sclerosis; SD: standard deviation; IFN-β: interferon-β; MP: methylprednisolone
Table 5. Statistical comparison of the serum IL-33 levels in patients with MS patients, according to their treatment program.
| Treatment | IFN-β | MP | IFN-β +MP | No treatment |
|---|---|---|---|---|
| IFN-β | - | 0.492 | 0.446 | 0.725 |
| MP | 0.492 | - | 0.649 | 0.443 |
| IFN-β+MP | 0.446 | 0.649 | - | 0.658 |
| No treatment | 0.725 | 0.443 | 0.658 | - |
| Control | 0.346 | 0.002 | 0.006 | 0.007 |
IFN-β: interferon-β; MP: methylprednisolone
No significant differences in serum IL-33 concentration were observed between patients with various MS patterns. Serum IL-33 concentrations in patients with RRMS, SPMS, and PPMS were significantly higher than the control group (p<0.006, p<0.001, and p<0.020, respectively) [Table 6].
Table 6. Serum levels of IL-33 in MS patients according to disease patterns.
| Group | Disease form |
Number | IL-33 levels* | p-value |
|---|---|---|---|---|
| MS | RRMS | 102 | 364.1±61.3 | 0.530 |
| SPMS | 28 | 567.2±155.3 | ||
| PPMS | 8 | 486.6±127.51 | ||
| PRMS | 2 | 374.6±375.1 | ||
| Total | 140 | 408.0±55.3 | ||
| Control | - | 140 | 156.7±35.4 |
*Values expressed as mean±SD. The serum levels of cytokine expressed as pg/ml. IL-33: interleukin-33; MS: multiple sclerosis; SD: standard deviation; PPMS: primary progressive multiple sclerosis; PRMS: progressive-relapsing multiple sclerosis; RRMS: relapsing-remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis.
Discussion
We observed increased concentrations of IL-33 in both serum and CSF samples from patients with MS, which suggests that IL-33 contributes to its pathogenesis. In both male and female patients with MS, the serum IL-33 concentrations were significantly higher compared to the control group subjects with the same gender. Accordingly, the elevated IL-33 concentrations may contribute to the pathogenesis of MS in both genders.
In female patients with MS disease, the mean CSF IL-33 concentration was also significantly higher compared to women in the control group. In male patients with MS disease, the mean CSF IL-33 concentration was also higher compared to men in the control group, but the difference was not statistically significant. This was probably due to a low sample size of men. The use of a suitable sample size of CSF from men in any future studies could clarify this association. Recent investigations have also indicated that IL-33 may be involved in the pathogenesis of chronic inflammatory diseases such as asthma, rheumatoid arthritis, and anaphylaxis suggesting that IL-33 may have potent pro-inflammatory characteristics.13,17
Attention has been focused on the role of IL-33 in the pathogenesis of immune-mediated CNS diseases due to very high levels of IL-33 mRNA expression in the brain and spinal cord.14 The IL-33 is produced by some cells such as keratinocytes, dendritic cells, activated macrophages, endothelial cells, epithelial cells, smooth muscle cells, and fibroblasts.18 Furthermore, IL-33 is mainly produced by astrocytes in murine spinal cord19 and human CNS tissues.20 This suggests that IL-33-producing astrocytes may contribute to innate immune responses in the CNS. Astrocytes also express the IL-33 receptor, and IL-33 expression by astrocytes was increased in response to inflammatory stimuli and toll-like receptor ligation.21 IL-33 levels were elevated in the periphery and CNS of MS patients, indicating that IL-33 may participate in the pathogenesis of MS disease.20
Higher expression of IL-33 mRNA in the CNS of EAE mice has been observe.22 Within the CNS, microglia cells are the main target of IL-33, which induces microglia proliferation, phagocytosis, and the secretion of inflammatory cytokines and chemokines.19 IL-33 induces the synthesis of IL-6, IL-13, and monocyte chemoattractant protein (MCP)-1 in microglia, and this induction is increased by IL-33-activated mast cells.21 The activated microglia cells have been introduced as important effector cells that contribute to the demyelination process in MS.23 IL-33 is also a potent endothelial activator that increases endothelial permeability in vitro and induces vascular leakage in mouse skin.24 As the breakdown of the blood-brain barrier (BBB) is an essential step for the subsequent CNS inflammation, IL-33 may contribute to MS and EAE inflammation by disrupting the BBB in addition to modulating the immune system. Importantly, IL-33 may also facilitate recruitment of leukocytes into the CNS.25
Our results showed no significant differences in IL-33 serum levels between untreated patients and treated patients with methylprednisolone or both IFN-β plus methylprednisolone. The serum IL-33 concentrations in MS patients treated with methylprednisolone or both interferon-β plus methylprednisolone were significantly higher than the control group. However, there was no significant difference between patients treated with IFN-β and the control group on serum IL-33 concentrations. These findings indicate that treatment with IFN-β is more effective than treatment with methylprednisolone or both of IFN-β plus methylprednisolone in reducing serum IL-33 concentrations. Accordingly, the immunomodulatory effects of IFN-β may perform, in part, through the suppression of the IL-33 production. In agreement with our results, it has also been reported that treatment with IFN-β decreases IL-33 expression in the plasma and peripheral blood mononuclear cells of patients with MS.20 In the absence of methylprednisolone, treatment with IFN-β may have reducing effects on the IL-33 levels whereas, in the presence of methylprednisolone, the IFN-β effects on IL-33 levels disappeared. Therefore, methylprednisolone may influence the IFN-β effects on IL-33 levels. The insignificant change in IL-33 levels observed between treated and untreated MS patients seems to indicate that this cytokine may not be associated with the immunomodulatory effect of methylprednisolone in MS. Moreover, it should be noted that the immunotherapeutic effects of IFN-β and methylprednisolone on the MS disease may be performed through their modulating effects on the other inflammatory and immunopathological parameters. Our results encourage further studies to investigate the influences of IFN-β and methylprednisolone on the IL-33 production.
IL-33 may be involved in the pathogenesis of all MS forms. We saw higher levels of IL-33 in patients with RRMS, SPMS, and PPMS forms of MS compared to the control group. The levels of IL-33 were also higher in patients with PRMS, but valid statistical analyzes require bigger sample size for this MS disease pattern.
Although high expression of IL-33 mRNA in the CNS of mice was also demonstrated,14 studies of its role in the development of EAE as an animal model of MS are controversial.26 IL-33 may have a preventive role in EAE at the initial (inducible) stage of the disease. However, after the establishment of EAE, it may have an enhancing role in the disease development due to the presence of some inflammatory cells in CNS. It has been reported that IL-33 induces both Th1- and Th2-related immune responses depending on the presence of certain conditions (i.e., the cytokine environment and cellular types).27 For example, IL-33 has synergistic effects with IL-1 and IL-18 to increasing Th1/Th17-related response in experimental arthritis.28 It has been also demonstrated that IL-33 stimulates IFN-γ synthesis by iNKT and NK cells.26 IL-33 also reinforces Th1/Th17-related immune responses in some experimental models of immune disorders.29 In IL-33-treated mice, the antigen-stimulated draining lymph nodes produce more IL-17 and IFN-γ.14 Accordingly, IL-33 may be involved in the pathogenesis of the EAE and MS through the reinforcement of Th17 and Th1 cell functions.
Conclusion
Our study showed increased concentrations of IL-33 in patients with MS. This included both untreated and treated patients, and those with RRMS, SPMS, and PPMS form of the disease. Accordingly, IL-33 may be involved in the pathogenesis of all MS forms, and treatment of MS patients with methylprednisolone or both IFN-β plus methylprednisolone have no influence on IL-33 concentrations.
Disclosure
The authors declared no conflicts of interest. No funding was received for this study.
References
- 1.Anlar O. Treatment of multiple sclerosis. CNS Neurol Disord Drug Targets 2009. Jun;8(3):167-174. 10.2174/187152709788680670 [DOI] [PubMed] [Google Scholar]
- 2.Haghmorad D, Mahmoudi MB, Mahmoudi M, Rab SZ, Rastin M, Shegarfi H, et al. Calcium intervention ameliorates experimental model of multiple sclerosis. Oman Med J 2014. May;29(3):185-189. 10.5001/omj.2014.46 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Mix E, Meyer-Rienecker H, Hartung H-P, Zettl UK. Animal models of multiple sclerosis–potentials and limitations. Prog Neurobiol 2010. Nov;92(3):386-404. 10.1016/j.pneurobio.2010.06.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Tumani H, Kassubek J, Hijazi M, Lehmensiek V, Unrath A, Süssmuth S, et al. Patterns of TH1/TH2 cytokines predict clinical response in multiple sclerosis patients treated with glatiramer acetate. Eur Neurol 2011;65(3):164-169. 10.1159/000324035 [DOI] [PubMed] [Google Scholar]
- 5.Rawji KS, Yong VW. The benefits and detriments of macrophages/microglia in models of multiple sclerosis. Clin Develop Immunol. 2013;2013. [DOI] [PMC free article] [PubMed]
- 6.Jafarzadeh A, Ebrahimi HA, Bagherzadeh S, Zarkesh F, Iranmanesh F, Najafzadeh A, et al. Lower serum levels of Th2-related chemokine CCL22 in women patients with multiple sclerosis: a comparison between patients and healthy women. Inflammation 2014. Apr;37(2):604-610. 10.1007/s10753-013-9775-z [DOI] [PubMed] [Google Scholar]
- 7.Jafarzadeh A, Bagherzadeh S, Ebrahimi HA, Hajghani H, Bazrafshani MR, Khosravimashizi A, et al. Higher circulating levels of chemokine CCL20 in patients with multiple sclerosis: evaluation of the influences of chemokine gene polymorphism, gender, treatment and disease pattern. J Mol Neurosci 2014. Jul;53(3):500-505. 10.1007/s12031-013-0214-2 [DOI] [PubMed] [Google Scholar]
- 8.Sattler S, Smits HH, Xu D, Huang FP. The evolutionary role of the IL-33/ST2 system in host immune defence. Arch Immunol Ther Exp (Warsz) 2013. Apr;61(2):107-117. 10.1007/s00005-012-0208-8 [DOI] [PubMed] [Google Scholar]
- 9.Komai-Koma M, Xu D, Li Y, McKenzie AN, McInnes IB, Liew FY. IL-33 is a chemoattractant for human Th2 cells. Eur J Immunol 2007. Oct;37(10):2779-2786. 10.1002/eji.200737547 [DOI] [PubMed] [Google Scholar]
- 10.Nakae S, Morita H, Ohno T, Arae K, Matsumoto K, Saito H. Role of interleukin-33 in innate-type immune cells in allergy. Allergol Int 2013. Mar;62(1):13-20. 10.2332/allergolint.13-RAI-0538 [DOI] [PubMed] [Google Scholar]
- 11.Milovanovic M, Volarevic V, Radosavljevic G, Jovanovic I, Pejnovic N, Arsenijevic N, et al. IL-33/ST2 axis in inflammation and immunopathology. Immunol Res 2012. Apr;52(1-2):89-99. 10.1007/s12026-012-8283-9 [DOI] [PubMed] [Google Scholar]
- 12.Bourgeois E, Van LP, Samson M, Diem S, Barra A, Roga S, et al. The pro-Th2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-γ production. Eur J Immunol 2009. Apr;39(4):1046-1055. 10.1002/eji.200838575 [DOI] [PubMed] [Google Scholar]
- 13.Nakae S, Morita H, Ohno T, Arae K, Matsumoto K, Saito H. Role of interleukin-33 in innate-type immune cells in allergy. Allergol Int 2013. Mar;62(1):13-20. 10.2332/allergolint.13-RAI-0538 [DOI] [PubMed] [Google Scholar]
- 14.Schmitz J, Owyang A, Oldham E, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. 2005;23(5):479–90. [DOI] [PubMed]
- 15.Li M, Li Y, Liu X, Gao X, Wang Y. IL-33 blockade suppresses the development of experimental autoimmune encephalomyelitis in C57BL/6 mice. J Neuroimmunol 2012. Jun;247(1-2):25-31. 10.1016/j.jneuroim.2012.03.016 [DOI] [PubMed] [Google Scholar]
- 16.McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001. Jul;50(1):121-127. 10.1002/ana.1032 [DOI] [PubMed] [Google Scholar]
- 17.Hayakawa H, Hayakawa M, Kume A, Tominaga S. Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J Biol Chem 2007. Sep;282(36):26369-26380. 10.1074/jbc.M704916200 [DOI] [PubMed] [Google Scholar]
- 18.Lloyd CM. IL-33 family members and asthma - bridging innate and adaptive immune responses. Curr Opin Immunol 2010. Dec;22(6):800-806. 10.1016/j.coi.2010.10.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Yasuoka S, Kawanokuchi J, Parajuli B, Jin S, Doi Y, Noda M, et al. Production and functions of IL-33 in the central nervous system. Brain Res 2011. Apr;1385:8-17. 10.1016/j.brainres.2011.02.045 [DOI] [PubMed] [Google Scholar]
- 20.Christophi GP, Gruber RC, Panos M, Christophi RL, Jubelt B, Massa PT. Interleukin-33 upregulation in peripheral leukocytes and CNS of multiple sclerosis patients. Clin Immunol 2012. Mar;142(3):308-319. 10.1016/j.clim.2011.11.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Hudson CA, Christophi GP, Gruber RC, Wilmore JR, Lawrence DA, Massa PT. Induction of IL-33 expression and activity in central nervous system glia. J Leukoc Biol 2008. Sep;84(3):631-643. 10.1189/jlb.1207830 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Jafarzadeh A, Mohammadi-Kordkhayli M, Ahangar-Parvin R, Azizi V, Khoramdel-Azad H, Shamsizadeh A, et al. Ginger extracts influence the expression of IL-27 and IL-33 in the central nervous system in experimental autoimmune encephalomyelitis and ameliorates the clinical symptoms of disease. J Neuroimmunol 2014. Nov;276(1-2):80-88. 10.1016/j.jneuroim.2014.08.614 [DOI] [PubMed] [Google Scholar]
- 23.Jack C, Ruffini F, Bar-Or A, Antel JP. Microglia and multiple sclerosis. J Neurosci Res 2005. Aug;81(3):363-373. 10.1002/jnr.20482 [DOI] [PubMed] [Google Scholar]
- 24.Choi Y-S, Choi H-J, Min J-K, Pyun BJ, Maeng YS, Park H, et al. Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. Blood 2009. Oct;114(14):3117-3126. 10.1182/blood-2009-02-203372 [DOI] [PubMed] [Google Scholar]
- 25.Iikura M, Suto H, Kajiwara N, Oboki K, Ohno T, Okayama Y, et al. IL-33 can promote survival, adhesion and cytokine production in human mast cells. Lab Invest 2007. Oct;87(10):971-978. 10.1038/labinvest.3700663 [DOI] [PubMed] [Google Scholar]
- 26.Milovanovic M, Volarevic V, Ljujic B, Radosavljevic G, Jovanovic I, Arsenijevic N, et al. Deletion of IL-33R (ST2) abrogates resistance to EAE in BALB/C mice by enhancing polarization of APC to inflammatory phenotype. PLoS One 2012;7(9):e45225. 10.1371/journal.pone.0045225 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Palmer G, Talabot-Ayer D, Lamacchia C, Toy D, Seemayer CA, Viatte S, et al. Inhibition of interleukin-33 signaling attenuates the severity of experimental arthritis. Arthritis Rheum 2009. Mar;60(3):738-749. 10.1002/art.24305 [DOI] [PubMed] [Google Scholar]
- 28.Nunes T, Bernardazzi C, de Souza HS. Interleukin-33 and inflammatory bowel diseases: lessons from human studies. Mediators Inflamm 2014;2014(423957):423957. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Rostami A, Ciric B. Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination. J Neurol Sci 2013. Oct;333(1-2):76-87. 10.1016/j.jns.2013.03.002 [DOI] [PMC free article] [PubMed] [Google Scholar]