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Proinflammatory TLR signalling is regulated by a TRAF2-dependent proteolysis mechanism in macrophages.

Jin J, Xiao Y, Hu H, Zou Q, Li Y, Gao Y, Ge W, Cheng X, Sun SC - Nat Commun (2015)

Bottom Line: TRAF2 deficiency does not enhance upstream signalling events, but it causes accumulation of two transcription factors, c-Rel and IRF5, known to mediate proinflammatory cytokine induction.We further show that TRAF2 also regulates inflammatory cytokine production in tumour-associated macrophages and facilitates tumour growth.These findings demonstrate an unexpected anti-inflammatory function of TRAF2 and suggest a proteasome-dependent mechanism that limits the proinflammatory TLR signalling.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.

ABSTRACT
Signal transduction from toll-like receptors (TLRs) is important for innate immunity against infections, but deregulated TLR signalling contributes to inflammatory disorders. Here we show that myeloid cell-specific ablation of TRAF2 greatly promotes TLR-stimulated proinflammatory cytokine expression in macrophages and exacerbates colitis in an animal model of inflammatory bowel disease. TRAF2 deficiency does not enhance upstream signalling events, but it causes accumulation of two transcription factors, c-Rel and IRF5, known to mediate proinflammatory cytokine induction. Interestingly, TRAF2 controls the fate of c-Rel and IRF5 via a proteasome-dependent mechanism that also requires TRAF3 and the E3 ubiquitin ligase cIAP. We further show that TRAF2 also regulates inflammatory cytokine production in tumour-associated macrophages and facilitates tumour growth. These findings demonstrate an unexpected anti-inflammatory function of TRAF2 and suggest a proteasome-dependent mechanism that limits the proinflammatory TLR signalling.

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TRAF2 negatively regulates proinflammatory cytokine induction(a,b) qRT-PCR analysis of the indicated genes using BMDMs (A) or peritoneal macrophages (b) derived from WT or Traf2-MKO mice at 0, 2 and 6 hours after LPS stimulation. Data are presented as fold relative to the Actin mRNA level. (c) ELISA of the indicated cytokines in the supernatants of the WT and Traf2-MKO BMDMs, which were either not treated (0) or stimulated with LPS for 24 h. Data are presented as mean ± SEM values and representative of at least three independent experiments. The error bars represent SD, and differences between experimental and control groups were determined by Student's t test. *P < 0.05; **P < 0.01.
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Figure 2: TRAF2 negatively regulates proinflammatory cytokine induction(a,b) qRT-PCR analysis of the indicated genes using BMDMs (A) or peritoneal macrophages (b) derived from WT or Traf2-MKO mice at 0, 2 and 6 hours after LPS stimulation. Data are presented as fold relative to the Actin mRNA level. (c) ELISA of the indicated cytokines in the supernatants of the WT and Traf2-MKO BMDMs, which were either not treated (0) or stimulated with LPS for 24 h. Data are presented as mean ± SEM values and representative of at least three independent experiments. The error bars represent SD, and differences between experimental and control groups were determined by Student's t test. *P < 0.05; **P < 0.01.

Mentions: To examine the mechanism by which TRAF2 regulates colitis, we analyzed the effect of TRAF2 deficiency on gene induction in macrophages by the TLR4 ligand LPS. Remarkably, the TRAF2-deficient bone marrow derived macrophages (BMDMs) were hyper-responsive to LPS in the induction of a number of proinflammatory cytokine genes and the iNOS gene (Nos2) (Fig. 2a). Conversely, the TRAF2 deficiency attenuated the induction of the anti-inflammatory cytokine gene Il10. Similar results were obtained using peritoneal macrophages isolated from the Traf2-MKO or WT control mice (Fig. 2b). The LPS-stimulated aberrant expression of proinflammatory cytokines in Traf2-MKO macrophages also occurred at the protein level, as revealed by ELISA (Fig. 2c).


Proinflammatory TLR signalling is regulated by a TRAF2-dependent proteolysis mechanism in macrophages.

Jin J, Xiao Y, Hu H, Zou Q, Li Y, Gao Y, Ge W, Cheng X, Sun SC - Nat Commun (2015)

TRAF2 negatively regulates proinflammatory cytokine induction(a,b) qRT-PCR analysis of the indicated genes using BMDMs (A) or peritoneal macrophages (b) derived from WT or Traf2-MKO mice at 0, 2 and 6 hours after LPS stimulation. Data are presented as fold relative to the Actin mRNA level. (c) ELISA of the indicated cytokines in the supernatants of the WT and Traf2-MKO BMDMs, which were either not treated (0) or stimulated with LPS for 24 h. Data are presented as mean ± SEM values and representative of at least three independent experiments. The error bars represent SD, and differences between experimental and control groups were determined by Student's t test. *P < 0.05; **P < 0.01.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4286812&req=5

Figure 2: TRAF2 negatively regulates proinflammatory cytokine induction(a,b) qRT-PCR analysis of the indicated genes using BMDMs (A) or peritoneal macrophages (b) derived from WT or Traf2-MKO mice at 0, 2 and 6 hours after LPS stimulation. Data are presented as fold relative to the Actin mRNA level. (c) ELISA of the indicated cytokines in the supernatants of the WT and Traf2-MKO BMDMs, which were either not treated (0) or stimulated with LPS for 24 h. Data are presented as mean ± SEM values and representative of at least three independent experiments. The error bars represent SD, and differences between experimental and control groups were determined by Student's t test. *P < 0.05; **P < 0.01.
Mentions: To examine the mechanism by which TRAF2 regulates colitis, we analyzed the effect of TRAF2 deficiency on gene induction in macrophages by the TLR4 ligand LPS. Remarkably, the TRAF2-deficient bone marrow derived macrophages (BMDMs) were hyper-responsive to LPS in the induction of a number of proinflammatory cytokine genes and the iNOS gene (Nos2) (Fig. 2a). Conversely, the TRAF2 deficiency attenuated the induction of the anti-inflammatory cytokine gene Il10. Similar results were obtained using peritoneal macrophages isolated from the Traf2-MKO or WT control mice (Fig. 2b). The LPS-stimulated aberrant expression of proinflammatory cytokines in Traf2-MKO macrophages also occurred at the protein level, as revealed by ELISA (Fig. 2c).

Bottom Line: TRAF2 deficiency does not enhance upstream signalling events, but it causes accumulation of two transcription factors, c-Rel and IRF5, known to mediate proinflammatory cytokine induction.We further show that TRAF2 also regulates inflammatory cytokine production in tumour-associated macrophages and facilitates tumour growth.These findings demonstrate an unexpected anti-inflammatory function of TRAF2 and suggest a proteasome-dependent mechanism that limits the proinflammatory TLR signalling.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.

ABSTRACT
Signal transduction from toll-like receptors (TLRs) is important for innate immunity against infections, but deregulated TLR signalling contributes to inflammatory disorders. Here we show that myeloid cell-specific ablation of TRAF2 greatly promotes TLR-stimulated proinflammatory cytokine expression in macrophages and exacerbates colitis in an animal model of inflammatory bowel disease. TRAF2 deficiency does not enhance upstream signalling events, but it causes accumulation of two transcription factors, c-Rel and IRF5, known to mediate proinflammatory cytokine induction. Interestingly, TRAF2 controls the fate of c-Rel and IRF5 via a proteasome-dependent mechanism that also requires TRAF3 and the E3 ubiquitin ligase cIAP. We further show that TRAF2 also regulates inflammatory cytokine production in tumour-associated macrophages and facilitates tumour growth. These findings demonstrate an unexpected anti-inflammatory function of TRAF2 and suggest a proteasome-dependent mechanism that limits the proinflammatory TLR signalling.

Show MeSH
Related in: MedlinePlus