In vivo knockdown of TAK1 accelerates bone marrow proliferation/differentiation and induces systemic inflammation.

TAK1 (TGF-β Activated Kinase 1) is a MAPK kinase kinase, which activates the p38- and JNK-MAPK and NF-κB pathways downstream of receptors such as Toll-Like-, cytokine- and T-cell and B-cell receptors. Representing such an important node in the pro-inflammatory signal-transduction network, the functi...

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Autores principales:	Paul M Vink, Wendy M Smout, Lilian J Driessen-Engels, Alex M de Bruin, Dianne Delsing, Magda A Krajnc-Franken, Aswin J Jansen, Eric F Rovers, André A van Puijenbroek, Allard Kaptein, Martijn A Nolte, Anja Garritsen, Hans van Eenennaam
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f155c1e5db6e4d95b71327873beac492
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spelling	oai:doaj.org-article:f155c1e5db6e4d95b71327873beac4922021-11-18T07:54:28ZIn vivo knockdown of TAK1 accelerates bone marrow proliferation/differentiation and induces systemic inflammation.1932-620310.1371/journal.pone.0057348https://doaj.org/article/f155c1e5db6e4d95b71327873beac4922013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23505428/?tool=EBIhttps://doaj.org/toc/1932-6203TAK1 (TGF-β Activated Kinase 1) is a MAPK kinase kinase, which activates the p38- and JNK-MAPK and NF-κB pathways downstream of receptors such as Toll-Like-, cytokine- and T-cell and B-cell receptors. Representing such an important node in the pro-inflammatory signal-transduction network, the function of TAK1 has been studied extensively. TAK1 knock-out mice are embryonic lethal, while conditional knock-out mice demonstrated either a pro- or anti-inflammatory function. To study the function of TAK1 protein in the adult immune system, we generated and characterized a transgenic mouse expressing TAK1 shRNA under the control of a doxycycline-inducible promoter. Following treatment of TAK-1 shRNA transgenic mice with doxycycline an effective knockdown of TAK1 protein levels was observed in lymphoid organs and cells in the peritoneal cavity (>50% down regulation). TAK1 knockdown resulted in significant changes in leukocyte populations in blood, bone marrow, spleen and peritoneal cavity. Upon TAK1 knockdown mice demonstrated splenomegaly, signs of systemic inflammation (increased levels of circulating cytokines and increase in cellularity of the B-cell areas and in germinal center development in the follicles) and degenerative changes in heart, kidneys and liver. Not surprisingly, TAK1-Tg mice treated with LPS or anti-CD3 antibodies showed enhanced cytokine/chemokine secretion. Finally, analysis of progenitor cells in the bone marrow upon doxycycline treatment showed increased proliferation and differentiation of myeloid progenitor cells. Given the similarity of the phenotype with TGF-β genetic models, our data suggest that in our model the function of TAK1 in TGF-β signal-transduction is overruling its function in pro-inflammatory signaling.Paul M VinkWendy M SmoutLilian J Driessen-EngelsAlex M de BruinDianne DelsingMagda A Krajnc-FrankenAswin J JansenEric F RoversAndré A van PuijenbroekAllard KapteinMartijn A NolteAnja GarritsenHans van EenennaamPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 3, p e57348 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Paul M Vink Wendy M Smout Lilian J Driessen-Engels Alex M de Bruin Dianne Delsing Magda A Krajnc-Franken Aswin J Jansen Eric F Rovers André A van Puijenbroek Allard Kaptein Martijn A Nolte Anja Garritsen Hans van Eenennaam In vivo knockdown of TAK1 accelerates bone marrow proliferation/differentiation and induces systemic inflammation.
description	TAK1 (TGF-β Activated Kinase 1) is a MAPK kinase kinase, which activates the p38- and JNK-MAPK and NF-κB pathways downstream of receptors such as Toll-Like-, cytokine- and T-cell and B-cell receptors. Representing such an important node in the pro-inflammatory signal-transduction network, the function of TAK1 has been studied extensively. TAK1 knock-out mice are embryonic lethal, while conditional knock-out mice demonstrated either a pro- or anti-inflammatory function. To study the function of TAK1 protein in the adult immune system, we generated and characterized a transgenic mouse expressing TAK1 shRNA under the control of a doxycycline-inducible promoter. Following treatment of TAK-1 shRNA transgenic mice with doxycycline an effective knockdown of TAK1 protein levels was observed in lymphoid organs and cells in the peritoneal cavity (>50% down regulation). TAK1 knockdown resulted in significant changes in leukocyte populations in blood, bone marrow, spleen and peritoneal cavity. Upon TAK1 knockdown mice demonstrated splenomegaly, signs of systemic inflammation (increased levels of circulating cytokines and increase in cellularity of the B-cell areas and in germinal center development in the follicles) and degenerative changes in heart, kidneys and liver. Not surprisingly, TAK1-Tg mice treated with LPS or anti-CD3 antibodies showed enhanced cytokine/chemokine secretion. Finally, analysis of progenitor cells in the bone marrow upon doxycycline treatment showed increased proliferation and differentiation of myeloid progenitor cells. Given the similarity of the phenotype with TGF-β genetic models, our data suggest that in our model the function of TAK1 in TGF-β signal-transduction is overruling its function in pro-inflammatory signaling.
format	article
author	Paul M Vink Wendy M Smout Lilian J Driessen-Engels Alex M de Bruin Dianne Delsing Magda A Krajnc-Franken Aswin J Jansen Eric F Rovers André A van Puijenbroek Allard Kaptein Martijn A Nolte Anja Garritsen Hans van Eenennaam
author_facet	Paul M Vink Wendy M Smout Lilian J Driessen-Engels Alex M de Bruin Dianne Delsing Magda A Krajnc-Franken Aswin J Jansen Eric F Rovers André A van Puijenbroek Allard Kaptein Martijn A Nolte Anja Garritsen Hans van Eenennaam
author_sort	Paul M Vink
title	In vivo knockdown of TAK1 accelerates bone marrow proliferation/differentiation and induces systemic inflammation.
title_short	In vivo knockdown of TAK1 accelerates bone marrow proliferation/differentiation and induces systemic inflammation.
title_full	In vivo knockdown of TAK1 accelerates bone marrow proliferation/differentiation and induces systemic inflammation.
title_fullStr	In vivo knockdown of TAK1 accelerates bone marrow proliferation/differentiation and induces systemic inflammation.
title_full_unstemmed	In vivo knockdown of TAK1 accelerates bone marrow proliferation/differentiation and induces systemic inflammation.
title_sort	in vivo knockdown of tak1 accelerates bone marrow proliferation/differentiation and induces systemic inflammation.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/f155c1e5db6e4d95b71327873beac492
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In vivo knockdown of TAK1 accelerates bone marrow proliferation/differentiation and induces systemic inflammation.

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