TWEAK activates the non-canonical NFkappaB pathway in murine renal tubular cells: modulation of CCL21.

TWEAK is a member of the TNF superfamily of cytokines that contribute to kidney tubulointerstitial injury. It has previously been reported that TWEAK induces transient nuclear translocation of RelA and expression of RelA-dependent cytokines in renal tubular cells. Additionally, TWEAK induced long-la...

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Autores principales:	Ana B Sanz, Maria D Sanchez-Niño, Maria C Izquierdo, Aniela Jakubowski, Pilar Justo, Luis M Blanco-Colio, Marta Ruiz-Ortega, Rafael Selgas, Jesús Egido, Alberto Ortiz
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0689c36edf4b4682a5e19199a677282d
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spelling	oai:doaj.org-article:0689c36edf4b4682a5e19199a677282d2021-11-25T06:26:15ZTWEAK activates the non-canonical NFkappaB pathway in murine renal tubular cells: modulation of CCL21.1932-620310.1371/journal.pone.0008955https://doaj.org/article/0689c36edf4b4682a5e19199a677282d2010-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20126461/?tool=EBIhttps://doaj.org/toc/1932-6203TWEAK is a member of the TNF superfamily of cytokines that contribute to kidney tubulointerstitial injury. It has previously been reported that TWEAK induces transient nuclear translocation of RelA and expression of RelA-dependent cytokines in renal tubular cells. Additionally, TWEAK induced long-lasting NFkappaB activation suggestive of engagement of the non-canonical NFkappaB pathway. We now explore TWEAK-induced activation of NFkappaB2 and RelB, as well as expression of CCL21, a T-cell chemotactic factor, in cultured murine tubular epithelial cells and in healthy kidneys in vivo. In cultured tubular cells, TWEAK and TNFalpha activated different DNA-binding NFkappaB complexes. TWEAK-induced sustained NFkappaB activation was associated with NFkappaB2 p100 processing to p52 via proteasome and nuclear translocation and DNA-binding of p52 and RelB. TWEAK, but not TNFalpha used as control), induced a delayed increase in CCL21a mRNA (3.5+/-1.22-fold over control) and CCL21 protein (2.5+/-0.8-fold over control), which was prevented by inhibition of the proteasome, or siRNA targeting of NIK or RelB, but not by RelA inhibition with parthenolide. A second NFkappaB2-dependent chemokine, CCL19, was upregulates by TWEAK, but not by TNFalpha. However, both cytokines promoted chemokine RANTES expression (3-fold mRNA at 24 h). In vivo, TWEAK induced nuclear NFkappaB2 and RelB translocation and CCL21a mRNA (1.5+/-0.3-fold over control) and CCL21 protein (1.6+/-0.5-fold over control) expression in normal kidney. Increased tubular nuclear RelB and tubular CCL21 expression in acute kidney injury were decreased by neutralization (2+/-0.9 vs 1.3+/-0.6-fold over healthy control) or deficiency of TWEAK (2+/-0.9 vs 0.8+/-0.6-fold over healthy control). Moreover, anti-TWEAK treatment prevented the recruitment of T cells to the kidney in this model (4.1+/-1.4 vs 1.8+/-1-fold over healthy control). Our results thus identify TWEAK as a regulator of non-canonical NFkappaB activation and CCL21 expression in tubular cells thus promoting lymphocyte recruitment to the kidney during acute injury.Ana B SanzMaria D Sanchez-NiñoMaria C IzquierdoAniela JakubowskiPilar JustoLuis M Blanco-ColioMarta Ruiz-OrtegaMarta Ruiz-OrtegaRafael SelgasJesús EgidoAlberto OrtizPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 1, p e8955 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ana B Sanz Maria D Sanchez-Niño Maria C Izquierdo Aniela Jakubowski Pilar Justo Luis M Blanco-Colio Marta Ruiz-Ortega Marta Ruiz-Ortega Rafael Selgas Jesús Egido Alberto Ortiz TWEAK activates the non-canonical NFkappaB pathway in murine renal tubular cells: modulation of CCL21.
description	TWEAK is a member of the TNF superfamily of cytokines that contribute to kidney tubulointerstitial injury. It has previously been reported that TWEAK induces transient nuclear translocation of RelA and expression of RelA-dependent cytokines in renal tubular cells. Additionally, TWEAK induced long-lasting NFkappaB activation suggestive of engagement of the non-canonical NFkappaB pathway. We now explore TWEAK-induced activation of NFkappaB2 and RelB, as well as expression of CCL21, a T-cell chemotactic factor, in cultured murine tubular epithelial cells and in healthy kidneys in vivo. In cultured tubular cells, TWEAK and TNFalpha activated different DNA-binding NFkappaB complexes. TWEAK-induced sustained NFkappaB activation was associated with NFkappaB2 p100 processing to p52 via proteasome and nuclear translocation and DNA-binding of p52 and RelB. TWEAK, but not TNFalpha used as control), induced a delayed increase in CCL21a mRNA (3.5+/-1.22-fold over control) and CCL21 protein (2.5+/-0.8-fold over control), which was prevented by inhibition of the proteasome, or siRNA targeting of NIK or RelB, but not by RelA inhibition with parthenolide. A second NFkappaB2-dependent chemokine, CCL19, was upregulates by TWEAK, but not by TNFalpha. However, both cytokines promoted chemokine RANTES expression (3-fold mRNA at 24 h). In vivo, TWEAK induced nuclear NFkappaB2 and RelB translocation and CCL21a mRNA (1.5+/-0.3-fold over control) and CCL21 protein (1.6+/-0.5-fold over control) expression in normal kidney. Increased tubular nuclear RelB and tubular CCL21 expression in acute kidney injury were decreased by neutralization (2+/-0.9 vs 1.3+/-0.6-fold over healthy control) or deficiency of TWEAK (2+/-0.9 vs 0.8+/-0.6-fold over healthy control). Moreover, anti-TWEAK treatment prevented the recruitment of T cells to the kidney in this model (4.1+/-1.4 vs 1.8+/-1-fold over healthy control). Our results thus identify TWEAK as a regulator of non-canonical NFkappaB activation and CCL21 expression in tubular cells thus promoting lymphocyte recruitment to the kidney during acute injury.
format	article
author	Ana B Sanz Maria D Sanchez-Niño Maria C Izquierdo Aniela Jakubowski Pilar Justo Luis M Blanco-Colio Marta Ruiz-Ortega Marta Ruiz-Ortega Rafael Selgas Jesús Egido Alberto Ortiz
author_facet	Ana B Sanz Maria D Sanchez-Niño Maria C Izquierdo Aniela Jakubowski Pilar Justo Luis M Blanco-Colio Marta Ruiz-Ortega Marta Ruiz-Ortega Rafael Selgas Jesús Egido Alberto Ortiz
author_sort	Ana B Sanz
title	TWEAK activates the non-canonical NFkappaB pathway in murine renal tubular cells: modulation of CCL21.
title_short	TWEAK activates the non-canonical NFkappaB pathway in murine renal tubular cells: modulation of CCL21.
title_full	TWEAK activates the non-canonical NFkappaB pathway in murine renal tubular cells: modulation of CCL21.
title_fullStr	TWEAK activates the non-canonical NFkappaB pathway in murine renal tubular cells: modulation of CCL21.
title_full_unstemmed	TWEAK activates the non-canonical NFkappaB pathway in murine renal tubular cells: modulation of CCL21.
title_sort	tweak activates the non-canonical nfkappab pathway in murine renal tubular cells: modulation of ccl21.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/0689c36edf4b4682a5e19199a677282d
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TWEAK activates the non-canonical NFkappaB pathway in murine renal tubular cells: modulation of CCL21.

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