Skip Navigation


International Immunology Advance Access originally published online on December 22, 2005
International Immunology 2006 18(2):347-353; doi:10.1093/intimm/dxh373
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
18/2/347    most recent
dxh373v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (8)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Stark, J. L.
Right arrow Articles by Cross, A. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stark, J. L.
Right arrow Articles by Cross, A. H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?


© The Japanese Society for Immunology. 2005. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Differential expression of suppressors of cytokine signaling-1 and -3 and related cytokines in central nervous system during remitting versus non-remitting forms of experimental autoimmune encephalomyelitis

Jennifer L. Stark and Anne H. Cross

Department of Neurology and Neurosurgery, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8111, Saint Louis, MO 63110, USA

Correspondence to: J. L. Stark; E-mail: starkj{at}neuro.wustl.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
SJL mice exhibit a relapsing–remitting course of experimental autoimmune encephalomyelitis (EAE), whereas C57BL/6 (B6) mice display a more chronic course without complete remissions. Suppressor of cytokine signaling (SOCS)-1 and SOCS-3 are members of a family of inducible intracellular proteins that negatively regulate cytokine signaling in cells of hematopoietic origin and may influence the Th1 to Th2 balance. SOCS-1 and SOCS-3 are induced by cytokines that are known to be up-regulated during EAE, including IFN-gamma (IFN-g) and IL-6, respectively. To test the hypothesis that the level of induction of SOCS-1 and SOCS-3 correlates with the course of EAE, mRNA levels were compared in spinal cords of SJL and B6 mice during discrete stages of disease. SOCS-1 and SOCS-3 were elevated throughout active disease in both strains. At peak EAE, SOCS-1 was higher and SOCS-3 was lower in B6 cords compared with SJL cords. This correlated with greater expression of the Th1 cytokine, IFN-g, and less of the Th2 cytokine, IL-10, in B6 cords relative to SJL cords during onset and peak disease. SOCS-3 inducers in the IL-6 family were expressed differentially between the strains. IL-6 and leukemia inhibitory factor were higher at onset in B6 cords whereas ciliary neurotrophic factor was increased in SJL cords during peak disease. Expression of fibroblast growth factor-2, which may be involved in remyelination, was higher in SJL cords at peak. Comparison of these models suggests that cytokine autoregulatory mechanisms involving SOCS may play a role in determining the course of EAE.

Keywords: cytokines, EAE, multiple sclerosis, SOCS-1, SOCS-3


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) that can be modeled by immunizing mice with myelin antigens. Most MS patients have a relapsing–remitting form of disease, in which there is nearly complete recovery between attacks, whereas others have progressive forms, in which neurologic impairment accumulates (1). It is not clear what immunological or neurological mechanisms determine disease course. Relapsing–remitting experimental autoimmune encephalomyelitis (EAE) is characterized by functional recovery following acute disease and can be induced by immunizing SJL mice with myelin proteins (2, 3). Immunization of C57BL/6 (B6) mice with myelin oligodendrocyte glycoprotein (MOG)35–55 yields a chronic form of EAE in which complete recovery does not occur (4).

Suppressor of cytokine signaling (SOCS)-1 and SOCS-3 are intracellular proteins that are induced by numerous cytokines and growth factors and regulate inflammatory responses by providing negative feedback to cytokine signaling pathways. SOCS-1 binds to Janus kinases (5), preventing activation of various cytokine signal transduction pathways. Mice lacking SOCS-1 die from organ damage at ~3 weeks of age due to unregulated IFN-gamma (IFN-g) actions (6). SOCS-3 deficiency is a lethal mutation, but studies using macrophages lacking SOCS-3 have shown that it negatively regulates the IL-6 pathway by binding to the gp130 receptor (7, 8).

Relative levels of SOCS-1 and SOCS-3 may reflect, as well as influence, the balance of Th1 and Th2 cytokines in the local environment. Naive CD4+ cells express low amounts of both SOCS-1 and SOCS-3, whereas SOCS-1 is elevated in Th1 cells and SOCS-3 is greatly increased in Th2 cells (9). In animal models, alteration of SOCS-3 levels can have beneficial or negative effects, depending on the nature of the immune process. Injection of adenoviral vectors containing SOCS-3 into the ankles of mice with antigen-induced arthritis reduced joint swelling, presumably by blocking the pathogenic effects of IL-6 (10). In contrast, SOCS-3 transgenic mice displayed increased severity of a Th2-mediated airway hypersensitivity (11). These studies suggest that the relative expression of SOCS-1 and SOCS-3 reflects the balance between Th1 and Th2 cytokines, which is thought to be important in regulating the course of EAE and perhaps MS.

The aim of the current experiments was to directly compare the expression of SOCS-1 and SOCS-3 in the spinal cords of SJL and B6 mice during EAE to determine if there was a relationship between SOCS and disease course. B6 CNS expressed relatively more SOCS-1 and less SOCS-3 than SJL CNS during peak disease. This pattern of SOCS expression in the B6 mice correlated with a Th1 cytokine profile, as well as delayed expression of growth factors that may be involved in remyelination. These molecular findings were associated with differences in EAE course and functional recovery between the two strains.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Induction and scoring of EAE
Female SJL/J and C57BL/6J mice were purchased from Jackson Laboratories (Bar Harbor, ME) and were housed in microisolater cages. Procedures were approved by the Washington University Animal Studies Committee. EAE was induced in SJL mice by immunizing with 500 µg bovine myelin emulsified (1:1) in CFA containing 60 µg of H37RA Mycobacterium tuberculosis (Difco Laboratories, Detroit, MI). B6 mice were immunized with 10 µg MOG35–55 (Sigma, St Louis, MO) emulsified (1:1) in CFA containing 50 µg H37RA M. tuberculosis. Control animals received injections of CFA without antigen or were age-matched naive. Each mouse received a total of 0.1 ml subcutaneously at two sites (base of neck and tail). Pertussis toxin (List Biological Laboratories, Inc.) was administered intravenously (100–200 ng for SJL and 300 ng for B6) at the time of immunization and 48–72 h later. Mice were scored according to the following scale: grade 0 = no observable neurologic impairments, grade 1 = limp tail, grade 2 = impaired righting reflex when animal is turned onto its back, grade 3 = paralysis of one hindlimb or impairment of both hindlimbs, grade 4 = paralysis of both hindlimbs and grade 5 = moribund or dead. EAE mice that were unable to reach food and water were provided with petri dishes of wet food inside the cage. Mice were sacrificed at different disease stages: pre-clinical = day 7 post-immunization with a grade of 0, onset = within 24 h of first sign of neurologic impairment, peak = grade 3.5–4.0 during acute disease, remission = improvement of at least one grade lasting at least 48 h following acute disease, relapse = worsening of at least one grade lasting at least 48 h following remission and chronic = unchanging clinical score for at least 10 days.

RNA isolation from spinal cords
Mice were deeply anesthetized and transcardially perfused with cold diethyl pyrocarbonate (DEPC)-treated PBS. Spinal cords were rapidly dissected, frozen in liquid nitrogen and stored at –80°C until RNA isolation. Each frozen spinal cord was homogenized in 1 ml RNA STAT-60 (TEL-TEST, Friendswood, TX) using a polytron. RNA was isolated according to the RNA STAT protocol, resuspended in DEPC-treated water and stored at –80°C.

Ribonuclease protection assay
The RiboQuant Multi-Probe Ribonuclease Protection Assay (RPA) (BD Biosciences, San Diego, CA) was used per manufacturer's instructions, with a custom mouse template set containing probes for SOCS-1, SOCS-3 and the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH). RNA (5 µg) was hybridized with {alpha}-32P-labeled probe and protected fragments were run on a urea–polyacrylamide gel. Dried gels were exposed to a phosphor screen (Molecular Dynamics/Amersham, Piscataway, NJ) and analyzed using a STORM 860 phosphorimager (Molecular Dynamics) and the Gel-Pro Analyzer 4.0 program (Media Cybernetics, Silver Spring, MD). The normalized intensity of each band was calculated as a percent of the GAPDH band for the same sample.

Quantitative (real-time) PCR
RNA was treated with deoxyribonuclease I (Sigma). cDNA was synthesized using random primers and SuperScript II reverse transcriptase (Invitrogen, Carlsbad, CA). Quantitative real-time PCR was performed on an ABI PRISM 7000 Sequence Detection System (Applied Biosystems, Foster City, CA) using SYBR Green JumpStart Taq ReadyMix (Sigma) and 1 µl of cDNA template per well. Primer pairs (Sigma-Genosys) for the housekeeping gene GAPDH, as well as the target genes, were determined using the Primer Express 2.0 program (Applied Biosystems). Primer efficiency was tested across a range of cDNA concentrations to ensure that it was similar to that of the GAPDH primers. Melting points of the PCR products were determined to confirm a single product. Samples were run in triplicate for 40 cycles to obtain threshold cycle (CT) values for GAPDH and target gene expression. Using 7000 SDS 1.1 Relative Quantification software (Applied Biosystems), target gene expression was first normalized to GAPDH expression. The relative quantitation to a calibrator group, which in this case was SJL naive spinal cords, was then calculated using the equation: 2–{Delta}{Delta}CT. By definition, this results in a value of 1.0 for the calibrator group. The pattern would have been the same if B6 naive cords had been the calibrator.

Statistical analyses
Statistical analyses were performed using Prism (GraphPad Software, Inc., San Diego, CA). Clinical EAE courses for SJL and B6 mice were compared by two-way analysis of variance. Student's t-tests were used to compare day of disease onset, peak SOCS expression and SOCS-1/SOCS-3 ratio between the two strains. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Clinical recovery from EAE occurs in SJL mice but not in B6 mice
The clinical courses of EAE for SJL and B6 mice were followed through day 37 post-immunization (Fig. 1). Disease onset occurred earlier in SJL mice than in B6 mice [12.7 ± 1.9 (SD) days post-immunization, n = 19 versus 15.1 ± 3.6 (SD), n = 17; P = 0.01]. Both strains reached similar peak disease scores, but B6 mice had a more severe disease course (P < 0.0001) with continued neurologic dysfunction, while SJL mice recovered from acute disease. Naive, CFA-immunized and pre-clinical mice from each strain, as well as EAE-affected mice at onset, peak, remission, relapse and chronic stages of disease, were sacrificed and spinal cords were removed for analysis of gene expression. Table 1 shows the details of the mice studied.


Figure 1
View larger version (22K):
[in this window]
[in a new window]
  		Fig. 1. Clinical course of EAE in SJL and B6 mice. The former were immunized with whole bovine myelin + CFA and the latter with MOG35–55 + CFA. Mice were scored for clinical signs of EAE beginning day 7 post-immunization. Scores are shown as mean ± SEM, with n = 4–19 per strain per time point.

 

View this table:
[in this window]
[in a new window]
  		Table 1. Summary of mice used in studies

 
SOCS-1 and SOCS-3 expression in SJL and B6 spinal cords during EAE
To determine if expression of SOCS-1 or SOCS-3 correlated with the different disease courses, spinal cord samples were analyzed by RPA. SOCS-3 mRNA was low and SOCS-1 mRNA was undetectable in naive, CFA-immunized and pre-clinical mice of both strains (Fig. 2A and B). At EAE onset, SOCS-3 was elevated to a similar degree in spinal cords from SJL and B6 mice. In SJL cords, expression of SOCS-3 mirrored active disease, as it remained high at peak, declined during remission and was again highly expressed at relapse. SOCS-3 expression progressively declined from the onset level during peak and chronic EAE in B6 mice. SOCS-1 showed a similar pattern to SOCS-3 in each strain, but was expressed at lower levels. During peak disease, SOCS-1 expression was higher in B6 mice (P = 0.007) and SOCS-3 levels were higher in SJL mice (P = 0.0001).


Figure 2
View larger version (16K):
[in this window]
[in a new window]
  		Fig. 2. Expression of SOCS-1 and SOCS-3 in CNS of SJL and B6 mice during EAE. Spinal cords were removed from naive, CFA-immunized, pre-clinical or EAE-affected mice at different disease stages. RNA was extracted and samples were analyzed by RPA. Expression for SOCS-1 and SOCS-3 was calculated as a percent of the housekeeping gene GAPDH in the same sample. Results are shown for SJL (A) and B6 (B) mice as mean + SEM, with n = 4–5 per group. In (C) SOCS-1/SOCS-3 ratios were calculated for onset, peak, remission (SJL only), relapse (SJL only) and chronic (B6 only) groups and are shown as mean + SEM.

 
Th1/Th2 profile in SJL and B6 spinal cords during EAE
SOCS-1 is reported to be preferentially expressed in Th1 cells and SOCS-3 in Th2 cells (9). The SOCS-1/SOCS-3 ratio, which may reflect the relative Th1/Th2 profile, was calculated for SJL and B6 mice during different stages of EAE (Fig. 2C). At disease peak, B6 cords had a significantly greater SOCS-1/SOCS-3 ratio (P < 0.001) than SJL cords, suggesting a more Th1, pro-inflammatory CNS environment. During chronic disease, the ratio in B6 cords dropped to the level seen in cords of sick SJL mice. The ratio was zero in SJL cords during remission due to a lack of SOCS-1 expression.

To assess the cytokine environment, real-time PCR was used to measure expression of IFN-g, a Th1 cytokine and inducer of SOCS-1, and IL-10, a Th2 cytokine and inducer of SOCS-3. Expression of both cytokines was similar in the control and pre-clinical groups for each strain. During acute disease, remission and relapse, spinal cords from SJL mice (Fig. 3A) showed increased expression of both IFN-g and IL-10 relative to naive SJL cords. In onset and peak B6 cords, IFN-g was up-regulated ~4-fold more than SJL cords at the same clinical stage. IFN-g remained high during chronic disease in B6 mice, whereas IL-10 was only slightly elevated (Fig. 3B).


Figure 3
View larger version (21K):
[in this window]
[in a new window]
  		Fig. 3. Expression of Th1 and Th2 cytokines in CNS of SJL and B6 mice during EAE. Spinal cords were removed from naive, CFA-immunized, pre-clinical or EAE mice at different disease stages. RNA was extracted and samples were analyzed by quantitative PCR. Expression of IFN-g and IL-10 was normalized to the housekeeping gene GAPDH and the expression for each group was calculated relative to the SJL naive group. Results are shown for SJL (A) and B6 (B) mice as mean ± 95% confidence interval, with n = 3 (for remission) to 5 per group.

 
Expression of IL-6-type cytokines and growth factors during EAE
Since a relative abundance of SOCS-3 mRNA was associated with a better clinical course of disease, real-time PCR was used to quantify the expression of IL-6-related cytokines, which are known to induce SOCS-3 in the CNS (12). These factors were differentially expressed in SJL versus B6 cords during acute disease. At disease onset, IL-6 was greatly up-regulated, with higher expression in B6 cords (Fig. 4A). At peak EAE, IL-6 decreased but remained high in both strains. IL-6 levels declined to near baseline during remission and chronic disease and increased again in SJL cords during relapse. Leukemia inhibitory factor (LIF) displayed a similar expression pattern to IL-6 (Fig. 4B). Ciliary neurotrophic factor (CNTF) expression remained stable in SJL cords until peak disease, when it increased ~2-fold and remained elevated during remission and relapse. Induction of CNTF in cords of B6 EAE mice was delayed until the chronic phase (Fig. 4C). Expression of fibroblast growth factor (FGF)-2, which is induced by CNTF in CNS cells (13) and has been associated with remyelination (14), was increased 3- to 4-fold in SJL cords during peak, remission and relapse stages (Fig 4D). Similar levels of expression in B6 mice were not seen until the chronic phase of EAE.


Figure 4
View larger version (32K):
[in this window]
[in a new window]
  		Fig. 4. Expression of SOCS-3 inducing cytokines and growth factors in CNS of SJL and B6 mice during EAE. Spinal cords were removed from naive, CFA-immunized, pre-clinical or EAE mice at different disease stages. RNA was extracted and samples were analyzed by quantitative PCR. Expression of IL-6 (A), LIF (B), CNTF (C) and FGF-2 (D) was normalized to the housekeeping gene GAPDH and the expression for each group was calculated relative to the SJL naive group. Results are shown as mean ± 95% confidence interval, with n = 3 (for remission) to 5 per group.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The hypothesis underlying these studies was that SOCS-1 and SOCS-3, endogenous negative feedback regulators of cytokine and growth factor actions, play a role in inducing the spontaneous remissions typical of SJL EAE. To address this, CNS expression of SOCS-1 and SOCS-3 in this relapsing–remitting model was compared with that in the chronic, non-remitting B6 model. The largest difference between the two strains occurred during peak EAE. Interestingly, this was immediately prior to the divergence of the clinical courses. At peak, B6 cords displayed higher SOCS-1 and lower SOCS-3 levels compared with SJL cords, resulting in a higher SOCS-1/SOCS-3 ratio. This was associated with greatly elevated expression of the pro-inflammatory cytokine, IFN-g, which both induces and is regulated by SOCS-1. Compared with SJL CNS, spinal cords from EAE-affected B6 mice at peak disease expressed lower levels of the SOCS-3 inducer, IL-10, as well as of the oligodendrocyte survival factors, CNTF and FGF-2. These data suggest that the failure of B6 mice to completely recover after acute EAE may be due to inadequate production of SOCS-3 in association with a predominantly pro-inflammatory CNS environment and a delay in expression of neuroprotective factors.

Although there is controversy about the roles of specific cytokines in MS and EAE, our data support the notion that the Th1 cytokine IFN-g is associated with clinical signs of disease whereas the Th2 cytokine IL-10 may promote recovery from acute EAE. The most striking finding was the extremely high levels of IFN-g expression in B6 cords from onset through the chronic phase of disease, indicating a Th1-skewed CNS environment. It is likely that the increased expression of SOCS-1 during active disease in both strains was due to this cytokine. SOCS-1 inhibits the functional responses of IFN-g and other cytokines by inhibiting JAK–STAT pathways (5), but would not necessarily be expected to alter protein or RNA levels of cytokines. In SJL mice, the increase in IFN-g during active disease was balanced by up-regulated IL-10, resulting in a relatively more Th2-like CNS environment. Increased CNS IL-10 has been implicated in recovery from acute EAE in a number of studies. In an adoptive transfer model of relapsing–remitting EAE, remissions were characterized by increased IL-10 in the spinal cord (15). Furthermore, IL-10-deficient mice do not undergo spontaneous recovery of EAE (16). A recent study found that remission was related to IL-10-secreting CD25+CD4+ regulatory T cells infiltrating the CNS (17).

During EAE, it is likely that localized production of cytokines and growth factors by numerous cell types determines the expression of downstream molecules such as SOCS. Similar to our findings, Maier et al. reported increased expression of SOCS-1 and SOCS-3 in B6 spinal cord and brain. Using in situ hybridization, expression of SOCS was primarily seen in mononuclear cells infiltrating the CNS (18). Other studies have shown that SOCS-1 and SOCS-3 are expressed in the embryonic and adult mouse brain (19) and can be induced in murine astrocytes (20). Therefore, the regulatory pathways activated during EAE may involve both infiltrating and endogenous cells within the complex CNS environment.

The data presented show that a relative abundance of SOCS-3 expression in the spinal cord during peak EAE correlates with remission, but suggest that not all SOCS-3 inducers have the same effects. In various cell types, SOCS-3 is up-regulated by IL-10 (21), as well as IL-6 (22), and the related cytokines, LIF and CNTF (12). In these experiments, higher IL-6 expression in B6 cords at EAE onset did not correlate with improved disease outcome. Members of the IL-6 family share the gp130 receptor, but are known to differentially affect the course of EAE. IL-6-deficient mice are resistant to active induction of EAE (23, 24), perhaps due to a shift towards Th2 cytokine production (25). The presence of endogenous CNTF (26) or exogenous administration of LIF (27) results in less severe EAE and enhanced oligodendrocyte survival. Surprisingly, in the current studies, higher expression of LIF during EAE onset in B6 mice correlated with a poorer disease outcome. This may be due to the fact that over-expression of LIF in the CNS has pro-inflammatory actions (28). In contrast, CNTF has been implicated in the protection of oligodendrocytes from tumor necrosis factor-induced cell death in vitro (29) and in vivo (26). The present studies suggest that induction of SOCS-3 during peak EAE may be involved in subsequent remission. However, more studies must be done to clarify whether SOCS-3 is contributing to recovery from acute EAE, or is merely a marker of a favorable cytokine environment.

The combination of elevated CNTF and FGF-2 in spinal cords of SJL mice during peak disease may create an environment which promotes remyelination. CNTF has been shown to enhance myelin formation in vitro (30). Although the role of FGF-2 in remyelination is controversial, it is known to stimulate the proliferation of oligodendrocyte precursors (31). In a murine viral model of demyelination, increased expression of CNTF during the remyelination phase was implicated in the stimulation of spinal cord FGF-2 (13). Increased FGF-2 expression in the same model coincided with recovery of neurologic function (14). Treatment of EAE mice with a vector expressing FGF-2 increased the number of oligodendrocyte precursor cells in damaged areas of the CNS and ameliorated disease (32).

EAE is often used as an animal model for MS, but few studies have taken advantage of the fact that different mouse strains show divergent courses of EAE. We have directly compared a remitting and a non-remitting model of EAE to investigate differences in CNS immune regulation and regenerative potential. The SJL and B6 models show similarities to the distinct disease courses exhibited by MS patients. Further investigations into the differences in EAE course among mouse strains may help us to understand the factors underlying the transition from relapsing–remitting MS to secondary progressive MS, and to develop neuroprotective therapies to complement the currently available immunomodulatory therapies.


   Acknowledgements
 
We are grateful for the excellent technical assistance of Nathan Allen, Bob Mikesell and Michael Ramsbottom. Neville S. Rapp offered helpful suggestions on the manuscript. These studies were funded by the National MS Society (PP0824) and the Barnes-Jewish Hospital Foundation. The ABI Prism 7000 was donated for MS research by Linda and Ken Slavin.


   Abbreviations
 
B6   C57BL/6
CNS   central nervous system
CNTF   ciliary neurotrophic factor
CT   threshold cycle
DEPC   diethyl pyrocarbonate
EAE   experimental autoimmune encephalomyelitis
FGF-2   fibroblast growth factor-2
GAPDH   glyceraldehyde-3-phosphate dehydrogenase
IFN-g   IFN-gamma
LIF   leukemia inhibitory factor
MOG   myelin oligodendrocyte glycoprotein
MS   multiple sclerosis
SOCS   suppressor of cytokine signaling

   Notes
 
Transmitting editor: L. Steinman

Received 15 March 2005, accepted 21 November 2005.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Lublin, F. D. and Reingold, S. C. 1996. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 46:907.[Abstract/Free Full Text]
  2. Fritz, R. B., Chou, C.-H. J. and McFarlin, D. E. 1983. Relapsing murine experimental allergic encephalomyelitis induced by myelin basic protein. J. Immunol. 130:1024.[Abstract]
  3. McRae, B. L., Kennedy, M. K., Tan, L.-J., Dal Canto, M. C., Picha, K. S. and Miller, S. D. 1992. Induction of active and adoptive relapsing experimental autoimmune encephalomyelitis (EAE) using an encephalitigenic epitope of proteolipid protein. J. Neuroimmunol. 38:229.[CrossRef][Web of Science][Medline]
  4. Slavin, A., Ewing, C., Liu, J., Ichikawa, M., Slavin, J. and Bernard, C. C. A. 1998. Induction of a multiple sclerosis-like disease in mice with an immunodominant epitope of myelin oligodendrocyte glycoprotein. Autoimmunity 28:109.[Web of Science][Medline]
  5. Endo, T. A., Masuhara, M., Yokouchi, M. et al. 1997. A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387:921.[CrossRef][Medline]
  6. Alexander, W. S., Starr, R., Fenner, J. E. et al. 1999. SOCS1 is a critical inhibitor of interferon {gamma} signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98:597.[CrossRef][Web of Science][Medline]
  7. Lang, R., Pauleau, A.-L., Parganas, E. et al. 2003. SOCS3 regulates the plasticity of gp130 signaling. Nat. Immunol. 4:546.[CrossRef][Web of Science][Medline]
  8. Yasukawa, H., Ohishi, M., Mori, H. et al. 2003. IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat. Immunol. 4:551.[CrossRef][Web of Science][Medline]
  9. Egwuagu, C. E., Yu, C.-R., Zhang, M., Mahdi, R. M., Kim, S. J. and Gery, I. 2002. Suppressors of cytokine signaling proteins are differentially expressed in Th1 and Th2 cells: implications for Th cell lineage commitment and maintenance. J. Immunol. 168:3181.[Abstract/Free Full Text]
  10. Shouda, T., Yoshida, T., Hanada, T. et al. 2001. Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J. Clin. Investig. 108:1781.[CrossRef][Web of Science][Medline]
  11. Seki, Y., Inoue, H., Nagata, N. et al. 2003. SOCS-3 regulates onset and maintenance of TH2-mediated allergic responses. Nat. Med. 9:1047.[CrossRef][Web of Science][Medline]
  12. Wang, J. and Campbell, I. L. 2002. Cytokine signaling in the brain: putting a SOCS in it? J. Neurosci. Res. 67:423.[CrossRef][Web of Science][Medline]
  13. Albrecht, P. J., Murtie, J. C., Ness, J. K. et al. 2003. Astrocytes produce CNTF during the remyelination phase of viral-induced spinal cord demyelination to stimulate FGF-2 production. Neurobiol. Dis. 13:89.[CrossRef][Web of Science][Medline]
  14. Messersmith, D. J., Murtie, J. C., Le, T. Q., Frost, E. E. and Armstrong, R. C. 2000. Fibroblast growth factor 2 (FGF2) and FGF receptor expression in an experimental demyelinating disease with extensive remyelination. J. Neurosci. Res. 62:241.[CrossRef][Web of Science][Medline]
  15. Kennedy, M. K., Torrance, D. S., Picha, K. S. and Mohler, K. M. 1992. Analysis of cytokine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery. J. Immunol. 149:2496.[Abstract]
  16. Samoilova, E. B., Horton, J. L. and Chen, Y. 1998. Acceleration of experimental autoimmune encephalomyelitis in interleukin-10-deficient mice: roles of interleukin-10 in disease progression and recovery. Cell. Immunol. 188:118.[CrossRef][Web of Science][Medline]
  17. McGeachy, M. J., Stephens, L. A. and Anderton, S. M. 2005. Natural recovery and protection from autoimmune encephalomyelitis: contribution of CD4+CD25+ regulatory cells within the central nervous system. J. Immunol. 175:3025.[Abstract/Free Full Text]
  18. Maier, J., Kincaid, C., Pagenstecher, A. and Campbell, I. L. 2002. Regulation of signal transducer and activator of transcription and suppressor of cytokine-signaling gene expression in the brain of mice with astrocyte-targeted production of interleukin-12 or experimental autoimmune encephalomyelitis. Am. J. Pathol. 160:271.[Abstract/Free Full Text]
  19. Polizzotto, M. N., Bartlett, P. F. and Turnley, A. M. 2000. Expression of "suppressor of cytokine signalling" (SOCS) genes in the developing and adult nervous system. J. Comp. Neurol. 423:348.[CrossRef][Web of Science][Medline]
  20. Stark, J. L., Lyons, J.-A. and Cross, A. H. 2004. Interferon-gamma produced by encephalitogenic cells induces suppressors of cytokine signaling in primary murine astrocytes. J. Neuroimmunol. 151:195.[CrossRef][Web of Science][Medline]
  21. Donnelly, R. P., Dickensheets, H. and Finbloom, D. S. 1999. The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes. J. Interferon Cytokine Res. 19:563.[CrossRef][Web of Science][Medline]
  22. Starr, R., Willson, T. A., Viney, E. M. et al. 1997. A family of cytokine-inducible inhibitors of signaling. Nature 387:917.[CrossRef][Medline]
  23. Mendel, I., Katz, A., Kozak, N., Ben-Nun, A. and Revel, M. 1998. Interleukin-6 functions in autoimmune encephalomyelitis: a study in gene-targeted mice. Eur. J. Immunol. 28:1727.[CrossRef][Web of Science][Medline]
  24. Samoilova, E. B., Horton, J. L., Hilliard, B., Liu., T.-S. T. and Chen, Y. 1998. IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J. Immunol. 161:6480.[Abstract/Free Full Text]
  25. Okuda, Y., Sakoda, S., Saeki, Y., Kishimoto, T. and Yanagihara, T. 2000. Enhancement of Th2 response in IL-6-deficient mice immunized with myelin oligodendrocyte glycoprotein. J. Neuroimmunol. 105:120.[CrossRef][Web of Science][Medline]
  26. Linker, R. A., Maurer, M., Gaupp, S. et al. 2002. CNTF is a major protective factor in demyelinating CNS disease: a neurotrophic cytokine as modulator in neuroinflammation. Nat. Med. 8:620.[CrossRef][Web of Science][Medline]
  27. Butzkueven, H., Zhang, J.-G., Soilu-Hanninen, M. et al. 2002. LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival. Nat. Med. 8:613.[CrossRef][Web of Science][Medline]
  28. Kerr, B. J. and Patterson, P. H. 2004. Potent pro-inflammatory actions of leukemia inhibitory factor in the spinal cord of the adult mouse. Exp. Neurol. 188:391.[CrossRef][Web of Science][Medline]
  29. Louis, J. C., Magal, E., Takayama, S. and Varon, S. 1993. CNTF protection of oligodendrocytes against natural and tumor necrosis factor-induced death. Science 259:689.[Abstract/Free Full Text]
  30. Stankoff, B., Aigrot, M.-S., Noel, F., Wattilliaux, A., Zalc, B. and Lubetzki, C. 2002. Ciliary neurotrophic factor (CNTF) enhances myelin formation: a novel role for CNTF and CNTF-related molecules. J. Neurosci. 22:9221.[Abstract/Free Full Text]
  31. Bansal, R. 2002. Fibroblast growth factors and their receptors in oligodendrocyte development: implications for demyelination and remyelination. Dev. Neurosci. 24:35.[CrossRef][Web of Science][Medline]
  32. Ruffini, F., Furlan, R., Poliani, P. L. et al. 2001. Fibroblast growth factor-II gene therapy reverts the clinical course and the pathological signs of chronic experimental autoimmune encephalomyelitis in C57BL/6 mice. Gene Ther. 8:1207.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Immunol.Home page
H. Qin, S. A. Niyongere, S. J. Lee, B. J. Baker, and E. N. Benveniste
Expression and Functional Significance of SOCS-1 and SOCS-3 in Astrocytes
J. Immunol., September 1, 2008; 181(5): 3167 - 3176.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
D. C. Fitzgerald, B. Ciric, T. Touil, H. Harle, J. Grammatikopolou, J. D. Sarma, B. Gran, G.-X. Zhang, and A. Rostami
Suppressive Effect of IL-27 on Encephalitogenic Th17 Cells and the Effector Phase of Experimental Autoimmune Encephalomyelitis
J. Immunol., September 1, 2007; 179(5): 3268 - 3275.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
M. A. Taubman, X. Han, K. B. LaRosa, S. S. Socransky, and D. J. Smith
Periodontal Bacterial DNA Suppresses the Immune Response to Mutans Streptococcal Glucosyltransferase
Infect. Immun., August 1, 2007; 75(8): 4088 - 4096.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
18/2/347    most recent
dxh373v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (8)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Stark, J. L.
Right arrow Articles by Cross, A. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stark, J. L.
Right arrow Articles by Cross, A. H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?