title: TWEAK (tumor necrosis factor-like weak inducer of apoptosis) activates CXCL16 expression during renal tubulointerstitial inflammation.
abstract: TWEAK (tumor necrosis factor-like weak inducer of apoptosis) is a TNF superfamily cytokine that activates the fibroblast growth factor-inducible 14 (Fn14) receptor. Transcriptional analysis of experimental kidney tubulointerstitial inflammation showed a correlation between an upregulation of the mRNA for the transmembrane chemokine CXCL16, a T-cell chemoattractant, and Fn14 activation. Exogenous TWEAK increased mouse kidney CXCL16 expression and T-lymphocyte infiltration in vivo, processes inhibited by the NF-κB inhibitor parthenolide. Tubular cell CXCL16 was increased in a nephrotoxic tubulointerstitial inflammation model and neutralizing anti-TWEAK antibodies decreased this CXCL16 expression and lymphocyte infiltration. In human kidney biopsies with tubulointerstitial inflammation, tubular cell CXCL16 and Fn14 expressions were associated with inflammatory infiltrates. TWEAK upregulated CXCL16 mRNA expression in cultured renal tubular cells in an NF-κB-dependent manner and increased soluble and cellular CXCL16 protein. CXCL16 modestly promoted the expression of cytokines in tubular cells expressing its receptor (CXCR6) and appeared to synergize with TWEAK to promote an inflammatory response; however, it did not modulate tubular cell proliferation or survival. Thus, TWEAK upregulates the expression of the chemokine CXCL16 in tubular epithelium and this may contribute to kidney tubulointerstitial inflammation.
authors.affiliation: IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid and Fundación Renal Iñigo Álvarez de Toledo, Madrid, Spain.
authors.forename: María Concepción
authors.initials: MC
authors.lastname: Izquierdo
authors.forename: Ana B
authors.initials: AB
authors.lastname: Sanz
authors.forename: Sergio
authors.initials: S
authors.lastname: Mezzano
authors.forename: Julia
authors.initials: J
authors.lastname: Blanco
authors.forename: Susana
authors.initials: S
authors.lastname: Carrasco
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Sanchez-Niño
authors.forename: Alberto
authors.initials: A
authors.lastname: Benito-Martín
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
mesh_terms: D000328:Adult; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001706:Biopsy; D002460:Cell Line; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6 / Q000235:genetics / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism*; D002633:Chemotaxis; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D005260:Female; D005492:Folic Acid; D020869:Gene Expression Profiling; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051116:Receptors, Scavenger / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D000074050:TWEAK Receptor; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D057134:Antibodies, Neutralizing; C423727:CXCL16 protein, human; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; D019743:Chemokines, CXC; C498926:Cxcl16 protein, mouse; D000074049:Cytokine TWEAK; D016328:NF-kappa B; D012333:RNA, Messenger; D051116:Receptors, Scavenger; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D012717:Sesquiterpenes; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; C002669:parthenolide; D005492:Folic Acid