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

• Published in: PloS one 2013-03, Vol.8 (3), p.e57348-e57348
• Main Authors: Vink, Paul M, Smout, Wendy M, Driessen-Engels, Lilian J, de Bruin, Alex M, Delsing, Dianne, Krajnc-Franken, Magda A, Jansen, Aswin J, Rovers, Eric F, van Puijenbroek, André A, Kaptein, Allard, Nolte, Martijn A, Garritsen, Anja, van Eenennaam, Hans
• Format: Article
• Language: English
• Subjects: Agriculture; Analysis; Animal models; Animals; Antibodies; Autoimmune diseases; Biology; Bone marrow; Bone Marrow - immunology; Bone Marrow - metabolism; Bone Marrow Cells - cytology; Bone Marrow Cells - enzymology; Bone Marrow Cells - immunology; Bone morphogenetic proteins; CD3 antigen; Cell Differentiation; Cell Proliferation; Cells (biology); Cytokines; Cytokines - biosynthesis; Differentiation; Disease Models, Animal; Doxycycline; Drinking water; Embryos; Follicles; Gene Knockdown Techniques; Genetic engineering; Growth factors; Heart; Homeostasis - genetics; Homeostasis - immunology; Immune system; Immunology; Inflammation; Inflammation - enzymology; Inflammation - genetics; Inflammation - immunology; Inflammatory bowel disease; Inflammatory diseases; JNK protein; Kidney - immunology; Kidney - metabolism; Kidney - pathology; Kidneys; Kinases; Laboratories; Leukocytes; Lipopolysaccharides; Liver; Liver - immunology; Liver - metabolism; Liver - pathology; Lymphocyte Activation - immunology; Lymphocytes - immunology; Lymphocytes - metabolism; Lymphocytes B; Lymphocytes T; MAP kinase; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - metabolism; Medicine; Mice; Mice, Transgenic; Myocardium - immunology; Myocardium - metabolism; Myocardium - pathology; NF-κB protein; Organs; Osteoprogenitor cells; Peritoneum; Proteins; Receptors; Rheumatoid arthritis; RNA Interference; Rodents; Signal transduction; Signaling; Spleen; Spleen - immunology; Spleen - metabolism; Spleen - pathology; Splenomegaly; T cells; TAK1 protein; Transforming growth factors; Transgenic animals; Transgenic mice; Vaccines
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0057348

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.