Bruton's tyrosine kinase is required for TLR-induced IL-10 production.
Bruton's tyrosine kinase (Btk) is a critical signaling mediator downstream of the B cell Ag receptor. X-linked agammaglobulinemia is caused by mutations in Btk resulting in multiple defects in B cell development and function, and recurrent bacterial infections. Recent evidence has also supported a role for Btk in TLR signaling. We demonstrate that Btk is activated by TLR4 in primary macrophages and is required for normal TLR-induced IL-10 production in multiple macrophage populations. Btk-deficient bone marrow-derived macrophages secrete decreased levels of IL-10 in response to multiple TLR ligands, compared with wild-type (WT) cells. Similarly, Btk-deficient peritoneal and splenic macrophages secrete decreased IL-10 levels compared with WT cultures. This phenotype correlates with Btk-dependent induction of NF-kappaB and AP-1 DNA binding activity, and altered commensal bacteria populations. Decreased IL-10 production may be responsible for increased IL-6 because blocking IL-10 in WT cultures increased IL-6 production, and supplementation of IL-10 to Btk-deficient cultures decreased IL-6 production. Similarly, injection of IL-10 in vivo with LPS decreases the elevated IL-6 serum levels during endotoxemia in Btk-deficient mice. These data further support a role for Btk in regulating TLR-induced cytokine production from APCs and provide downstream targets for analysis of Btk function.
Schmidt
Nathan W
NW
Department of Pediatrics, H. B. Wells Center for Pediatric Research and Walther Oncology Center, Indiana University School of Medicine, and Walther Cancer Institute, Indianapolis, IN 46202, USA.
Thieu
Vivian T
VT
Mann
Brandon A
BA
Ahyi
Ayele-Nati N
AN
Kaplan
Mark H
MH
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001420:Bacteria, Aerobic / Q000254:growth & development / Q000276:immunology; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D015850:Interleukin-6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D016753:Interleukin-10; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse