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Mincle-mediated translational regulation is required for strong nitric oxide production and inflammation resolution.

Lee WB, Kang JS, Choi WY, Zhang Q, Kim CH, Choi UY, Kim-Ha J, Kim YJ - Nat Commun (2016)

Bottom Line: Here we show that Mincle, the inducible receptor for mycobacterial cord factor, is the key switch for the transition of macrophages from cytokine expression to high nitric oxide production.In addition to its stimulatory role on TLR-mediated transcription, Mincle enhanced the translation of key genes required for nitric oxide synthesis through p38 and eIF5A hypusination, leading to granuloma resolution.Thus, Mincle has dual functions in the promotion and subsequent resolution of inflammation during anti-mycobacterial defence using both transcriptional and translational controls.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.

ABSTRACT
In response to persistent mycobacteria infection, the host induces a granuloma, which often fails to eradicate bacteria and results in tissue damage. Diverse host receptors are required to control the formation and resolution of granuloma, but little is known concerning their regulatory interactions. Here we show that Mincle, the inducible receptor for mycobacterial cord factor, is the key switch for the transition of macrophages from cytokine expression to high nitric oxide production. In addition to its stimulatory role on TLR-mediated transcription, Mincle enhanced the translation of key genes required for nitric oxide synthesis through p38 and eIF5A hypusination, leading to granuloma resolution. Thus, Mincle has dual functions in the promotion and subsequent resolution of inflammation during anti-mycobacterial defence using both transcriptional and translational controls.

No MeSH data available.


Related in: MedlinePlus

Mincle-induced p38 activation is required for iNOS translation.(a,b) WT BMDMs were stimulated with TDM or Pam3 or co-stimulated with Pam3 and TDM in the presence of the indicated chemical inhibitors, for 12 h. (a) Nitric oxide production in culture supernatants. ***P<0.001 (Student's t-test). (b) left: qRT-PCR analysis of iNOS mRNA levels from stimulated macrophages; right: immunoblot analysis of iNOS protein expression. (c) Immunoblot analysis of phospho-p38 from WT and Mincle−/− BMDMs treated with Pam3, TDM or co-stimulated with Pam3 and TDM for 1 or 12 h. Data are representative of at least three independent experiments.
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f4: Mincle-induced p38 activation is required for iNOS translation.(a,b) WT BMDMs were stimulated with TDM or Pam3 or co-stimulated with Pam3 and TDM in the presence of the indicated chemical inhibitors, for 12 h. (a) Nitric oxide production in culture supernatants. ***P<0.001 (Student's t-test). (b) left: qRT-PCR analysis of iNOS mRNA levels from stimulated macrophages; right: immunoblot analysis of iNOS protein expression. (c) Immunoblot analysis of phospho-p38 from WT and Mincle−/− BMDMs treated with Pam3, TDM or co-stimulated with Pam3 and TDM for 1 or 12 h. Data are representative of at least three independent experiments.

Mentions: We previously found that TDM-induced Mincle signalling activates MAP kinases via Syk17. So we investigated whether these MAP kinases were involved in regulating iNOS translation. MAP kinase inhibitors had no effect (p38 inhibitor, SB203580 and Jnk inhibitor, SP600125) or enhanced (Erk inhibitor, U0126) NO release under Pam3 stimulation. However, the p38 inhibitor, SB203580 strongly and specifically inhibited NO release induced by Pam3 and TDM co-treatment (Fig. 4a). SB203580 appears to inhibit post-transcriptionally iNOS protein expression, but not mRNA expression, induced by Pam3 and TDM co-stimulation (Fig. 4b). Similarly, SB203580 also blocked TDM-dependent iNOS protein expression under LPS and TDM co-stimulation (Supplementary Fig. 11a,b). In addition, another p38 selective inhibitor, PD169316 also suppressed iNOS protein expression specifically (Supplementary Fig. 12a,b). Therefore, p38 activation appears to be required for Mincle-mediated iNOS protein expression.


Mincle-mediated translational regulation is required for strong nitric oxide production and inflammation resolution.

Lee WB, Kang JS, Choi WY, Zhang Q, Kim CH, Choi UY, Kim-Ha J, Kim YJ - Nat Commun (2016)

Mincle-induced p38 activation is required for iNOS translation.(a,b) WT BMDMs were stimulated with TDM or Pam3 or co-stimulated with Pam3 and TDM in the presence of the indicated chemical inhibitors, for 12 h. (a) Nitric oxide production in culture supernatants. ***P<0.001 (Student's t-test). (b) left: qRT-PCR analysis of iNOS mRNA levels from stimulated macrophages; right: immunoblot analysis of iNOS protein expression. (c) Immunoblot analysis of phospho-p38 from WT and Mincle−/− BMDMs treated with Pam3, TDM or co-stimulated with Pam3 and TDM for 1 or 12 h. Data are representative of at least three independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4837483&req=5

f4: Mincle-induced p38 activation is required for iNOS translation.(a,b) WT BMDMs were stimulated with TDM or Pam3 or co-stimulated with Pam3 and TDM in the presence of the indicated chemical inhibitors, for 12 h. (a) Nitric oxide production in culture supernatants. ***P<0.001 (Student's t-test). (b) left: qRT-PCR analysis of iNOS mRNA levels from stimulated macrophages; right: immunoblot analysis of iNOS protein expression. (c) Immunoblot analysis of phospho-p38 from WT and Mincle−/− BMDMs treated with Pam3, TDM or co-stimulated with Pam3 and TDM for 1 or 12 h. Data are representative of at least three independent experiments.
Mentions: We previously found that TDM-induced Mincle signalling activates MAP kinases via Syk17. So we investigated whether these MAP kinases were involved in regulating iNOS translation. MAP kinase inhibitors had no effect (p38 inhibitor, SB203580 and Jnk inhibitor, SP600125) or enhanced (Erk inhibitor, U0126) NO release under Pam3 stimulation. However, the p38 inhibitor, SB203580 strongly and specifically inhibited NO release induced by Pam3 and TDM co-treatment (Fig. 4a). SB203580 appears to inhibit post-transcriptionally iNOS protein expression, but not mRNA expression, induced by Pam3 and TDM co-stimulation (Fig. 4b). Similarly, SB203580 also blocked TDM-dependent iNOS protein expression under LPS and TDM co-stimulation (Supplementary Fig. 11a,b). In addition, another p38 selective inhibitor, PD169316 also suppressed iNOS protein expression specifically (Supplementary Fig. 12a,b). Therefore, p38 activation appears to be required for Mincle-mediated iNOS protein expression.

Bottom Line: Here we show that Mincle, the inducible receptor for mycobacterial cord factor, is the key switch for the transition of macrophages from cytokine expression to high nitric oxide production.In addition to its stimulatory role on TLR-mediated transcription, Mincle enhanced the translation of key genes required for nitric oxide synthesis through p38 and eIF5A hypusination, leading to granuloma resolution.Thus, Mincle has dual functions in the promotion and subsequent resolution of inflammation during anti-mycobacterial defence using both transcriptional and translational controls.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.

ABSTRACT
In response to persistent mycobacteria infection, the host induces a granuloma, which often fails to eradicate bacteria and results in tissue damage. Diverse host receptors are required to control the formation and resolution of granuloma, but little is known concerning their regulatory interactions. Here we show that Mincle, the inducible receptor for mycobacterial cord factor, is the key switch for the transition of macrophages from cytokine expression to high nitric oxide production. In addition to its stimulatory role on TLR-mediated transcription, Mincle enhanced the translation of key genes required for nitric oxide synthesis through p38 and eIF5A hypusination, leading to granuloma resolution. Thus, Mincle has dual functions in the promotion and subsequent resolution of inflammation during anti-mycobacterial defence using both transcriptional and translational controls.

No MeSH data available.


Related in: MedlinePlus