Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Jul 1;189(1):33-7.
doi: 10.4049/jimmunol.1200470. Epub 2012 May 30.

Cutting edge: TNF receptor-associated factor 4 restricts IL-17-mediated pathology and signaling processes

Jarod A Zepp  1 , Caini Liu, Wen Qian, Ling Wu, Muhammet F Gulen, Zizhen Kang, Xiaoxia Li
Affiliations

Cutting edge: TNF receptor-associated factor 4 restricts IL-17-mediated pathology and signaling processes

Jarod A Zepp et al. J Immunol. .

Abstract

The effector T cell subset, Th17, plays a significant role in the pathogenesis of multiple sclerosis and of other autoimmune diseases. The signature cytokine, IL-17, engages the IL-17R and recruits the E3-ligase NF-κB activator 1 (Act1) upon stimulation. In this study, we examined the role of TNFR-associated factor (TRAF)4 in IL-17 signaling and Th17-mediated autoimmune encephalomyelitis. Primary cells from TRAF4-deficient mice displayed markedly enhanced IL-17-activated signaling pathways and induction of chemokine mRNA. Adoptive transfer of MOG35-55 specific wild-type Th17 cells into TRAF4-deficient recipient mice induced an earlier onset of disease. Mechanistically, we found that TRAF4 and TRAF6 used the same TRAF binding sites on Act1, allowing the competition of TRAF4 with TRAF6 for the interaction with Act1. Taken together, the results of this study reveal the necessity of a unique role of TRAF4 in restricting the effects of IL-17 signaling and Th17-mediated disease.

PubMed Disclaimer

Figures

Figure 1
Figure 1. The Role of TRAF4 in IL-17 induced signaling and gene expression
(A) Western analyses of lysates of primary kidney cells from TRAF4-deficient mice and littermate controls. (B) Western analyses of lysates of Hela cells transduced with retrovirus encoding hTRAF4. (C) Quantitative real-time PCR was performed on primary kidney cells from TRAF4-deficient mice and littermate controls. Gene expression levels relative to β-actin, n=5, means ± SEM, *p<0.05, **p<0.01 for control versus stimulated. The data shown represents experiments repeated three times.
Figure 2
Figure 2. TRAF4 deficiency exacerbates Th17 mediated EAE
(A) Serum cytokine concentration in TRAF4 deficient mice following intraperitoneal administration of IL-17 (2 µg/mouse for two days) (B) Clinical score of EAE severity. (C) Flow-cytometry of infiltrated immune cells in the brain at the peak of the disease. (D) Spinal cord gene expression at peak of disease relative to naïve TRAF4-deficient and control spinal cord RNA (E) Gene expression from primary astrocytes stimulated with IL-17 (50 ng/ml) for 16 hours. For (A) n=4 mice per group, for (D–E) quantitative real-time PCR was performed, gene expression is relative to β-actin. n=5 per group for (D) and n=2 (E), means ± SEM, *p<0.05, **p<0.01 for littermate control versus TRAF4-deficient. For adoptive transfer experiments n=5 per group, shown here is one of two independently performed experiments, ***p<0.001 determined by one-way ANOVA.
Figure 3
Figure 3. IL-17-induced Distinct Act1-TRAF interactions
Lysates from Act1-deficient MEFs restored with wild-type Act1 untreated or treated with IL-17 (50 ng/ml) were immunoprecipitated with anti-Act1 (A), anti-TRAF6 (B) and anti-TRAF4 (C), followed by Western analyses for the indicated proteins. Shown are representative of three independently performed assays.
Figure 4
Figure 4. TRAF4 restricts Act1/TRAF6 interaction
Lysates of primary kidney cells untreated and treated with IL-17 (50 ng/ml) were immunoprecipitated with anti-Act1 (A) and anti-TRAF6 (B), followed by Western analyses for the indicated proteins. (C) Lysates of MEFs transfected with TRAF4 or vector control, untreated or stimulated with IL-17 (50 ng/ml) were immunoprecipitated with anti-TRAF6, followed by Western analyses for the indicated proteins. (D) Lysates of Act1-deficient MEFs expressing WT Act1 or Act1-TBm untreated or stimulated with IL-17 (50 ng/ml) were immunoprecipitated with anti-TRAF4, followed by Western analyses for the indicated proteins. Shown are representative of three independently performed assays.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, Sudo K, Iwakura Y. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol. 2006;177:566–573. - PubMed
    1. Nakae S, Nambu A, Sudo K, Iwakura Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol. 2003;171:6173–6177. - PubMed
    1. Hu Y, Ota N, Peng I, Refino CJ, Danilenko DM, Caplazi P, Ouyang W. IL-17RC is required for IL-17A- and IL-17F-dependent signaling and the pathogenesis of experimental autoimmune encephalomyelitis. J Immunol. 2010;184:4307–4316. - PubMed
    1. Novatchkova M, Leibbrandt A, Werzowa J, Neubuser A, Eisenhaber F. The STIR-domain superfamily in signal transduction, development and immunity. Trends Biochem Sci. 2003;28:226–229. - PubMed
    1. Chang SH, Park H, Dong C. Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. J Biol Chem. 2006;281:35603–35607. - PubMed

Publication types

MeSH terms

LinkOut - more resources