• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Ann Rheum Dis. Author manuscript; available in PMC May 1, 2011.
Published in final edited form as:
PMCID: PMC2859101

Kinetic analysis of synovial signaling and gene expression in animal models of arthritis



Animal models of arthritis are frequently used to evaluate novel therapeutic agents. However, their ability to predict responses in humans is variable. We examined the time course of signaling molecule and gene expression in two models of arthritis to assist with selection of the model and timing of drug administration.


The passive K/BxN serum transfer and collagen-induced arthritis (CIA) models were studied. Activation of MAP kinase and IFN-response pathways was evaluated by Q-PCR and Western blot analysis of ankle joints at various time points during the models.


The kinetics of gene expression and kinase phosphorylation were strikingly different in passive K/BxN and CIA. All three MAP kinases (ERK, JNK, and p38) and upstream kinases were activated within days in passive K/BxN and, except for p38, declined as arthritis severity decreased. Surprisingly, IFN-regulated genes, including IRF7, were not induced in the model. In CIA, activation of ERK and JNK was surprisingly low, and p38 phosphorylation mainly peaked late in disease. IFN-response genes were activated during CIA, with especially prominent peaks at the onset of clinical arthritis.


Timing of treatment and selection of CIA or passive K/BxN could have an important impact on therapeutic response. p38, in particular, increases during the late stages of disease. ERK and JNK patterns are similar in passive K/BxN and RA, while IFN-response genes in CIA and RA were similar. The dichotomy between RA and animal models could help explain the poor correlation between efficacy in RA and pre-clinical studies.

Keywords: Rheumatoid arthritis, cytokines, inflammation, arthritis


Rheumatoid arthritis (RA) a chronic inflammatory disease marked by synovial inflammation and joint destruction.[1] Although treatment of RA has improved in the last decade, there is still a significant need for new therapies. The use of pre-clinical models of arthritis has played a key role in drug development to help bridge this gap. Many animal models have used to validate potential therapeutic targets. However, none are exact replicas of RA even though they might share some pathogenic mechanisms.[2] The accurate interpretation and use of rodent arthritis models, therefore, depends on understanding of how they relate to RA.

Discrepant results in human and rodent studies are well known and were recently reviewed in detail.[3] To improve the utility of the models in drug discovery, we profiled key molecules of the kinome and the interferon (IFN) response in murine arthritis systems that rely on innate immunity (passive K/BxN arthritis) or adaptive immunity (collagen-induced arthritis, or CIA). Our studies suggest that careful selection of models and the timing of therapy are critical variables that should be incorporated into target validation studies. By carefully designing these studies, the predictive value of thereby pre-clinical experiments can potentially be increased and expedite drug development.



C57BsL/6 and DBA1/J mice were purchased from The Jackson Laboratory (Bar Harbor, ME). All animal protocols received prior approval by the institutional review board.

Passive K/BxN arthritis

C57BL/6 recipient mice were injected with 100 µl of pooled adult K/BxN mice serum intraperitoneally on day 0 and 2.[4] Clinical arthritis scores were evaluated using a scale of 0–4 for each paw for a total score of 16. Four injected mice and 1 control mouse were sacrificed at each time point. Arthritis scores and incidence for each time point include only the mice sacrificed for mRNA and protein analysis.

Collagen-induced arthritis

DBA1/J mice were immunized with bovine type II collagen (1 mg/ml) in complete Freund’s adjuvant as previously described (Chondrex, Redmond, WA).[5, 6] On day 21, 100 µg of bovine type II collagen in 0.1 ml of PBS was injected intraperitoneally. On day 28, 5 µg of LPS 0111:B4 (Chondrex) in 0.1 ml of PBS was injected intraperitoneally to synchronize disease onset and decrease variability that would complicate the kinetic analysis. Clinical arthritis scores were evaluated using a scale of 0–4 for each paw for a total score of 16. Six immunized mice and 1 control mouse were sacrificed at each time point. Arthritis scores and incidence for each time point include only the mice sacrificed for mRNA and protein analysis.


Anti-MKK6 Ab was purchased from Stressgen (Ann Arbor, MI). Anti-P-Elk-1, anti-Elk-1, and anti-GAPDH Abs were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). All other antibodies were purchased from Cell Signaling Technology (Danvers, MA).

Western Blot Analysis

Snap frozen joints were pulverized and homogenized at 100 mg of tissue per 1 ml of lysis buffer. Western blot analysis was then performed on pooled samples from each time point as previously described.[7] Immunoreactive protein was detected with Immun-Star WesternC kit (Bio-Rad, Hercules, CA) using VersaDoc MP4000 imaging system (Bio-Rad). The densitometry analysis was done by using Quantity One 1-D analysis software (Bio-Rad).

Quantitative real-time PCR

RNA derived from snap frozen joint samples was isolated as described previously,[8] Quantitative realtime PCR was performed with Assays-on-Demand gene expression products (Applied Biosystems, Foster City, CA).[8] Sample threshold cycle (Ct) values were converted into cell equivalents (CE) of expression using a standard cDNA curve and normalized to the CE of Hprt1 expression to obtain relative cell expression units (REU).

Statistical Analysis

Data are expressed as mean ± SEM. Comparisons of Q-PCR data were performed by Student’s t test with Bonferroni’s correction where appropriate. For Western blot analysis, joint extracts for animals were pooled, which prevented formal statistical analysis.


Kinetic profile of gene expression and signaling in passive K/BxN serum arthritis

Clinical arthritis

Administration of K/BxN serum caused severe arthritis in all of the mice by day 4. Clinical scores increased through 8 and declined by day 12 (See Figure 1).

Figure 1
Disease severity scores in arthritis models. A. Clinical arthritis scores for passive K/BxN arthritis. Values are the mean ± SEM (n=4/time point; one of three experiments shown). B. Incidence of arthritis. C. Clinical arthritis scores for collagen-induced ...

Mediator gene expression

Initial experiments were performed to quantify gene expression in the joints of mice with passive K/BxN arthritis on days 0, 1, 4, 8, and 12 after serum administration. As shown in Figure 2, IL-6, IL-10 and MMP-3 expression increased within one day, which was before the onset of clinical arthritis. Expression of these genes remained high until day 8 and then decreased as disease severity declined. TNF expression was not increased, which is consistent with the observation that TNF plays a relatively modest role in this model compared with IL-1.[9] Of the IFN-response genes, which are defined by the presence of an IFN-specific response element (ISRE) in their promoters and identified using microarrays,[10, 11] IFNβ and RANTES mRNA expression surprisingly decreased during the course of the model. IP-10, however, increased early in disease and later returned to baseline.

Figure 2
Synovial cytokine gene expression in passive K/B×N arthritis and collagen-induced arthritis (CIA). A. Passive K/B×N arthritis. B. CIA. Articular mRNA expression was determined by quantitative real-time PCR and normalized to Hprt1. Joint ...

MAP kinase pathway

To determine the kinetic profile of MAP kinases in the joints of mice with K/BxN serum induced arthritis, Western blot analysis was performed. Joint extracts from each selected day were pooled to evaluate of multiple signaling pathways simultaneously. Phosphorylation of all three MAP kinases (p38, JNK, and ERK) increased within 1 day and peaked on day 4, which was when clinical scores reached their maximum level. JNK and ERK activation decreased on days 8 and 12 (Figure 3, Figure 4, and Figure 5 for p38, JNK, and ERK, respectively). However, P-p38 remained elevated even though clinical disease regressed.

Figure 3
Kinetics of p38 pathway activation in joints of mice with passive K/BxN arthritis and collagen-induced arthritis (CIA). Joint extracts were prepared and pooled for each time point. This process allowed us to determine mean expression but precluded formal ...
Figure 4
Kinetics of JNK pathway activation in joints of mice with passive K/B×N arthritis and collagen-induced arthritis (CIA). Joint extracts were prepared and pooled for each time point. A. Phosphorylation of each MAP kinase, its upstream kinase, and ...
Figure 5
Kinetics of ERK pathway activation in joints of mice with passive K/B×N arthritis and collagen-induced arthritis. Joint extracts were prepared and pooled for each time point. A. Phosphorylation of each MAP kinase, its upstream kinase, and substrate ...

The MKKs are upstream kinases that regulate the MAP kinases. While there is some overlap in their specificity, ERK is usually activated by MEK1 and 2, p38 by MKK3 and 6, and JNK by MKK4 and 7.[1214] The kinetics of MKK phosphorylation was generally similar to the MAP kinases (Figure 3, Figure 4, and Figure 5)..Late activation of P-p38 in the absence of P-MKK3/6 correlated best with P-MKK4 induction.[15] P-MKK7 levels were not be determined because the antibodies could not reliably detect this kinase in joint extracts (data not shown).

Activation of p38, JNK, and ERK substrates was also examined. Phosphorylation of MK2, a p38α substrate, was similar to the kinetics of p38. Phosphorylation of c-Jun, which is one of the main substrates of JNK, peaked on day 8. P-Elk-1, which is a substrate of ERK, persisted until day 12 despite a reduction in P-ERK levels, possibly because other kinases can activate this transcription factor.

IRF pathway

Studies of the IRF pathway focused on mRNA because as IKKε and IRF7 are transcriptionally regulated. Surprisingly, IRF3, IRF7, and IKKε gene expression either remained unchanged or decreased in the passive K/BxN model (see Figure 6). These results correlated with the lack of RANTES and IFNβ induction (see Figure 2).

Figure 6
Kinetics of IRF pathway activation in joints of mice with passive K/B×N arthritis and collagen-induced arthritis. Articular mRNA expression was determined by quantitative real-time PCR and normalized to Hprt1 for passive K/B×N (A) and ...

Kinetic profile of gene expression and signaling in collagen-induced arthritis

Clinical arthritis

Immunization with type II collagen caused severe arthritis in all mice, with synovitis beginning around day 30, peaking on day 40 (see Figure 1).

Mediator gene expression

The profile for gene expression in CIA is distinct from passive K/BxN arthritis (Figure 2). IL-6 expression increased markedly on day 30 but then decreased to near baseline. MMP3 expression, like IL-10, also increased by day 30 but persisted throughout while TNF was mainly expressed early in the model. The profile of IFN-response genes also differed from passive K/BxN, with a narrow window of markedly increased RANTES expression on day 30. IP-10 mRNA levels increased early but declined to baseline. As with the K/BxN experiment, IFNβ expression was below baseline at most time points.

MAP kinase pathway

p38 activation increased modestly during the early phases of the model, with a peak on day 20 (Figure 3). However, the major increase was delayed until when arthritis was well established. The JNK pathway was striking in that only the 54 kD isoforms was activated early in the model (Figure 4). Surprisingly, P-ERK did not increase during CIA (Figure 5).

MKK activation was also observed in CIA (Figure 3, Figure 4, and Figure 5). Of interest, P-MKK3/6 peaked early, which was temporally related only to the early P-p38 peak. P-MKK4 increased later in the model and correlated with delayed P-p38 expression. As with passive K/BxN, MKK4 and JNK activation did not correlate. MEK1/2 activation, like ERK, was not increased in CIA.

MAP kinase substrate activation in CIA was surprisingly modest (Figure 3, Figure 4, and Figure 5). c-Jun phosphorylation increased marginally. However, when P-c-Jun is normalized to total c-Jun instead of GAPDH, relative P-c-Jun levels increased by about 4-fold (data not shown). P-MK2 increases were quite modest, but occurred at the same time points as the P-p38 peaks.

IRF pathway

Activation of the IRF pathway in CIA correlated with IFN-response gene expression (see Figure 2 and Figure 6). IRF7 increased in the same window frame as RANTES. IKKε gene expression, which did not change in the passive model, was higher throughout CIA and peaked on day 30 when RANTES expression also was maximal. IRF3 expression was unchanged throughout the experiment, with a trend towards lower levels during CIA.


Mouse models of inflammatory arthritis are widely used to assess the utility of novel therapeutic agents. These models share many features with RA, but also differ from the human disease with respect to pathogenesis, relative contribution of innate and adaptive immunity, and diverse responses to therapeutic interventions.[2, 3, 16] The interpretation and rational use of pre-clinical models requires an understanding of each individual system and how it relates to RA, which is a heterogeneous disease that can involve multiple pathogenic mechanisms. The present study was designed to profile the kinetics of several key signaling pathways in murine arthritis, an approach that we previously used to evaluate the time course of AP-1 and NF-kB expression in CIA.[5] This information can be used to help determine the best ways to evaluate drugs in pre-clinical studies, including the model selection and the timing of drug administration (see Table 1 for a summary of results).

Table 1
Relative expression of genes and signaling molecules in passive K/BxN arthritis and collagen-induced arthritis.

Mouse passive K/BxN and active CIA were chosen because they are widely used and have distinct mechanisms. Passive K/BxN arthritis is an antibody-induced arthritis that is dependent solely on innate immunity, including complement, neutrophils, mast cells, and macrophages.[1719] In contrast, adaptive immunity participates in the pathogenesis of CIA through the generation of an antigen-specific response to type II collagen.[20]

MAP kinase inhibitors have been extensively studied in preclinical models of arthritis.[21] Despite abundant evidence that p38 inhibitors are effective in mice and rats, these observations have not yet translated to efficacy in humans.[22] Our profiling studies demonstrate that articular P-p38 levels generally correlate with clinical arthritis and proinflammatory mediator expression in early passive K/BxN arthritis and CIA. However, a second wave of P-p38 induction occurs during the late stages of both models when disease stabilizes or regresses. Early p38 activation was also associated with phosphorylation of its two main upstream kinases, namely MKK3 and MKK6. However, P-MKK3/6 induction was not observed in late disease. Instead, the MAP kinase kinase associated with P-p38 at these time points is MKK4, which can also activate p38.[15] These observations suggest that p38 might possess anti-inflammatory functions in established disease that are regulated by MKK4 rather than MKK3/6. Of interest, anti-inflammatory activity has been associated with p38, especially through the production of IL-10.[23] The fact that P-p38 levels do not correlate with IL-6 in CIA also suggests that the kinase might not tightly control some pro-inflammatory cytokines, especially in the late phases.

JNK was previously implicated as a therapeutic target in RA.[24] We observed that the patterns of JNK phosphorylation are distinct in passive K/BxN arthritis and CIA. Both major molecular weight species (54 kD and 46 kD) are phosphorylated in the former and correlate with synovitis and proinflammatory gene expression. However, only the high molecular weight protein was activated in CIA, with a peak on day 30 when many pro-inflammatory genes are activated. MKK4, which can phosphorylate JNK, was not induced during early phase of CIA, and MKK7 might be more important.[25]

The functions of individual JNK proteins vary depending on the cell lineage and mode of stimulation. The JNK family consists of JNK1, JNK2, and JNK3, each of which have multiple 54 kD and 46 kD isoforms due to alternative splicing.[26] Despite their biochemical and structural similarities, JNK1 and JNK2 exert distinct effects on c-Jun turnover and activity.[27] JNK2 is the major isoform of JNK family expressed by human FLS.[28] The 54 kD and 46 kD proteins are equally phosphorylated in cytokine-stimulated synoviocytes and RA synovium. This pattern suggests that passive K/BxN arthritis, rather than the CIA, might reflect JNK activation in RA and could be a better model for assessing JNK inhibitors.

One striking finding in our study was the lack of P-ERK and P-MEK1/2 in CIA compared with passive K/BxN arthritis. In contrast, P-Elk-1 was observed in both cases, probably because other kinases like JNK or p38 can phosphorylate this transcription factor.[29] Some ERK and MEK1/2 inhibitors are beneficial in CIA, which could be due to effects on central immunity rather than the synovium.[30, 31] Because P-ERK is expressed in RA synovium,[32] the ERK pathway in RA appears to correlate better with passive K/BxN arthritis than CIA.

The interferon signature has been implicated in many autoimmune and inflammatory diseases, including RA and systemic lupus erythematosus.[33, 34] The role of this pathway is complex; pre-clinical studies support the use of IFNβ itself as therapeutic agent while other suggest that blocking IFN-response genes with the ISRE in their promoters, like RANTES and IP-10, might be beneficial.[35] Therefore, we also evaluated the kinetics of IKKε, IRF3, and IRF7 gene expression in the joints of mice with passive K/BxN arthritis and CIA. IKKε is an IKK-related kinase that regulates IFN-mediated signaling and IFN-induced gene expression through IRF3 and IRF7 phosphorylation.[36] We measured mRNA expression for these genes rather than protein because the IKKε and IRF7 genes are induced by inflammation in addition to post-translational modification.[3741]

We were surprised to see either no change or a trend towards decreased IKKε and IRF7 expression in passive K/BxN arthritis. In contrast, the IRF pathway and IFN-regulated genes were highly activated in CIA. In some cases, as with IRF7, there was a spike in gene expression on day 30, a time when arthritis is accelerating. IRF7 expression correlated with synovial RANTES, both of which are regulated by IKKε.[42] As IKKε deficient mice have a modest reduction in the severity of arthritis in passive K/BxN arthritis, it might play a role in synovial innate immune responses.[43] Alternatively, the mechanism could be due to an effect on central immunity with an indirect effect on joints. IKKε is highly expressed and activated in RA synovial tissue, suggesting that CIA might be a more suitable model to evaluate interferon responses.[44]

In conclusion, the present study demonstrates distinct kinetic profiles of the MAP kinase families and IFN response molecules in models of arthritis. By tailoring studies to the mechanism of drug action, the signaling pathways, and the relationship between murine and rheumatoid synovial inflammation, a rational approach to pre-clinical models in drug testing can be developed. This process can potentially limit the number of models that need to be evaluated and enhance our ability to interpret the results.


The authors thank Meghan Edgar and Katharyn Topolewski for expert assistance. These studies were supported, in part, by NIH grants R01AI070555-R01AI067752, and R01AR47825.


To order reprints of this article go to: http://journals.bmj.com/cgi/reprintform

The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if accepted) to be published in Annals of the Rheumatic Diseases editions and any other BMJPGL products to exploit all subsidiary rights, as set out in our licence http://ard.bmjjournals.com/ifora/licence.pdf

The authors have no competing interests to declare.


1. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423:356–361. [PubMed]
2. Firestein GS. Rheumatoid arthritis in a mouse? Nat Clin Pract Rheumatol. 2009;5:1. [PMC free article] [PubMed]
3. Hegen M, Keith JC, Jr, Collins M, Nickerson-Nutter CL. Utility of animal models for identification of potential therapeutics for rheumatoid arthritis. Ann Rheum Dis. 2008;67:1505–1515. [PubMed]
4. Kouskoff V, Korganow AS, Duchatelle V, Degott C, Benoist C, Mathis D. Organ-specific disease provoked by systemic autoimmunity. Cell. 1996;87:811–822. [PubMed]
5. Han Z, Boyle DL, Manning AM, Firestein GS. AP-1 and NFκB regulation in rheumatoid arthritis and murine collagen-induced arthritis. Autoimmunity. 1998;28:197–208. [PubMed]
6. Wooley PH, Luthra HS, Stuart JM, David CS. Type II colagen-induced arthritis in mice. I. Major histocompatibility complex (I region) linkage and antibody correlates. J Exp Med. 1981;154:688–700. [PMC free article] [PubMed]
7. Hammaker DR, Boyle DL, Inoue T, Firestein GS. Regulation of the JNK pathway by TGF-beta activated kinase 1 in rheumatoid arthritis synoviocytes. Arthritis Res Ther. 2007;9:R57. [PMC free article] [PubMed]
8. Boyle DL, Rosengren S, Bugbee W, Kavanaugh A, Firestein GS. Quantitative biomarker analysis of synovial gene expression by real-time PCR. Arthritis Res Ther. 2003;5:R352–R360. [PMC free article] [PubMed]
9. Ji H, Pettit A, Ohmura K, Ortiz-Lopez A, Duchatelle V, Degott C, et al. Critical roles for interleukin 1 and tumor necrosis factor alpha in antibody-induced arthritis. J Exp Med. 2002;196:77–85. [PMC free article] [PubMed]
10. Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD. How cells respond to interferons. Annu Rev Biochem. 1998;67:227–264. [PubMed]
11. de Veer MJ, Holko M, Frevel M, Walker E, Der S, Paranjape JM, et al. Functional classification of interferon-stimulated genes identified using microarrays. J Leukoc Biol. 2001;69:912–920. [PubMed]
12. Schett G, Zwerina J, Firestein G. The p38 mitogen-activated protein kinase (MAPK) pathway in rheumatoid arthritis. Ann Rheum Dis. 2008;67:909–916. [PMC free article] [PubMed]
13. Sweeney SE, Firestein GS. Signal transduction in rheumatoid arthritis. Curr Opin Rheumatol. 2004;16:231–237. [PubMed]
14. Thalhamer T, McGrath MA, Harnett MM. MAPKs and their relevance to arthritis and inflammation. Rheumatology. 2008;47:409–414. [PubMed]
15. Brancho D, Tanaka N, Jaeschke A, Ventura JJ, Kelkar N, Tanaka Y, et al. Mechanism of p38 MAP kinase activation in vivo. Genes Dev. 2003;17:1969–1978. [PMC free article] [PubMed]
16. Firestein GS. The T cell cometh: interplay between adaptive immunity and cytokine networks in rheumatoid arthritis. J Clin Invest. 2004;114:471–474. [PMC free article] [PubMed]
17. Wipke BT, Allen PM. Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis. J Immunol. 2001;167:1601–1608. [PubMed]
18. Solomon S, Rajasekaran N, Jeisy-Walder E, Snapper SB, Illges H. A crucial role for macrophages in the pathology of K/B x N serum-induced arthritis. Eur J Immunol. 2005;35:3064–3073. [PubMed]
19. Chen M, Lam BK, Kanaoka Y, Nigrovic PA, Audoly LP, Austen KF, et al. Neutrophil-derived leukotriene B4 is required for inflammatory arthritis. J Exp Med. 2006;203:837–842. [PMC free article] [PubMed]
20. Brand DD, Kang AH, Rosloniec EF. Immunopathogenesis of collagen arthritis. Springer Semin Immunopathol. 2003;25:3–18. [PubMed]
21. Sweeney SE, Firestein GS. Mitogen activated protein kinase inhibitors: where are we now and where are we going? Ann Rheum Dis. 2006;65 suppl 3:iii83–iii88. [PMC free article] [PubMed]
22. Genovese MC. Inhibition of p38: has the fat lady sung? Arthritis Rheum. 2009;60:335–344.
23. Kim C, Sano Y, Todorova K, Carlson BA, Arpa L, Celada A, et al. The kinase p38 alpha serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression. Nat Immunol. 2008;9:1019–1027. [PMC free article] [PubMed]
24. Han Z, Boyle DL, Chang L, Bennett B, Karin M, Yang L, et al. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest. 2001;108:73–81. [PMC free article] [PubMed]
25. Inoue T, Hammaker D, Boyle DL, Firestein GS. Regulation of JNK by MKK-7 in fibroblast-like synoviocytes. Arthritis Rheum. 2006;54:2127–2135. [PubMed]
26. Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell. 2000;103:239–252. [PubMed]
27. Sabapathy K, Hochedlinger K, Nam SY, Bauer A, Karin M, Wagner EF. Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation. Mol Cell. 2004;15:713–725. [PubMed]
28. Han Z, Boyle DL, Aupperle KR, Bennett B, Manning AM, Firestein GS. Jun N-terminal kinase in rheumatoid arthritis. J Pharmacol Exp Ther. 1999;291:124–130. [PubMed]
29. Whitmarsh AJ, Yang SH, Su MS, Sharrocks AD, Davis RJ. Role of p38 and JNK mitogen-activated protein kinases in the activation of ternary complex factors. Mol Cell Biol. 1997;17:2360–2371. [PMC free article] [PubMed]
30. Ohori M, Takeuchi M, Maruki R, Nakajima H, Miyake H. FR180204, a novel and selective inhibitor of extracellular signal-regulated kinase, ameliorates collagen-induced arthritis in mice. Naunyn Schmiedebergs Arch Pharmacol. 2007;374:311–316. [PubMed]
31. Thiel MJ, Schaefer CJ, Lesch ME, Mobley JL, Dudley DT, Tecle H, et al. Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: potential proinflammatory mechanisms. Arthritis Rheum. 2007;56:3347–3357. [PubMed]
32. Schett G, Tohidast-Akrad M, Smolen JS, Schmid BJ, Steiner CW, Bitzan P, et al. Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal-regulated kinase, c-JUN N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis. Arthritis Rheum. 2000;43:2501–2512. [PubMed]
33. Theofilopoulos AN, Baccala R, Beutler B, Kono DH. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol. 2005;23:307–336. [PubMed]
34. Banchereau J, Pascual V. Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity. 2006;25:383–392. [PubMed]
35. Vervoordeldonk MJ, Aalbers CJ, Tak PP. Interferon beta for rheumatoid arthritis: new clothes for an old kid on the block. Ann Rheum Dis. 2009;68:157–158. [PubMed]
36. Häcker H, Karin M. Regulation and function of IKK and IKK-related kinases. Sci STKE. 2006;2006(357):re13. [PubMed]
37. Shimada T, Kawai T, Takeda K, Matsumoto M, Inoue J, Tatsumi Y, et al. IKK-i, a novel lipopolysaccharide-inducible kinase that is related to IkappaB kinases. Int Immunol. 1999;11:1357–1362. [PubMed]
38. Peters RT, Liao SM, Maniatis T. IKKepsilon is part of a novel PMA-inducible IkappaB kinase complex. Mol Cell. 2000;5:513–522. [PubMed]
39. Tamura T, Yanai H, Savitsky D, Taniguchi T. The IRF family transcription factors in immunity and oncogenesis. Annu Rev Immunol. 2008;26:535–584. [PubMed]
40. Aupperle KR, Yamanishi Y, Bennett BL, Mercurio F, Boyle DL, Firestein GS. Expression and regulation of inducible IkappaB kinase (IKK-i) in human fibroblast-like synoviocytes. Cell Immunol. 2001;214:54–59. [PubMed]
41. Sweeney SE, Mo L, Firestein GS. Antiviral gene expression in rheumatoid arthritis: role of IKKepsilon and interferon regulatory factor 3. Arthritis Rheum. 2007;56:743–752. [PubMed]
42. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, et al. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol. 2003;4:491–496. [PubMed]
43. Corr M, Boyle DL, Ronacher L, Flores N, Firestein GS. Synergistic benefit in inflammatory arthritis by targeting I kappaB kinase epsilon and interferon beta. Ann Rheum Dis. 2009;68:257–263. [PMC free article] [PubMed]
44. van Holten J, Smeets TJ, Blankert P, Tak PP. Expression of interferon beta in synovial tissue from patients with rheumatoid arthritis: comparison with patients with osteoarthritis and reactive arthritis. Ann Rheum Dis. 2005;64:1780–1782. [PMC free article] [PubMed]
PubReader format: click here to try


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • GSS
    Published GSS sequences
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...