Bruton's tyrosine kinase is dispensable for the Toll-like receptor-mediated activation of mast cells.
Bruton's tyrosine kinase (Btk) represents an important signaling element downstream of ITAM-containing receptors, e.g. FcepsilonR1 and BCR. Btk is part of the calcium signalosome and thus, critically involved in intracellular calcium mobilization. Loss of Btk or expression of mutant forms results in severe disease phenotypes, X-linked agammaglobulinemia (XLA) and Xid in humans and mice, respectively. Previously, roles for Btk in TLR-mediated signal transduction have been found in monocytes/macrophages. In the present study we show that Btk deficiency moderately enhances or has no influence on the LPS- or lipopeptide-induced secretion of IL-6 and TNF-alpha from murine bone marrow-derived mast cells (BMMCs). Furthermore, activation of p38 kinase, which is required for cytokine production, is comparable in WT and Btk-/- BMMCs. Moreover, stability of the adaptor protein Mal as well as LPS-induced H(2)O(2) production does not vary between WT and Btk-/- cells. Interestingly, PKC-beta deficiency, which results in a Xid-like phenotype as well, has also no negative effect on LPS-induced cytokine secretion, suggesting that proteins of the calcium signalosome are not involved in TLR-mediated BMMC activation. In conclusion, the study reveals that Btk is dispensable for TLR signaling and function in murine BMMCs.
Zorn
Carolin N
CN
Department of Molecular Immunology, Biology III, Albert-Ludwigs-University Freiburg and Max-Planck-Institute for Immunobiology, 79108 Freiburg, Germany.
Keck
Simone
S
Hendriks
Rudi W
RW
Leitges
Michael
M
Freudenberg
Marina A
MA
Huber
Michael
M
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D015850:Interleukin-6 / Q000032:analysis / Q000378:metabolism; D055666:Lipopeptides / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D009000:Monocytes / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000577:Amides; D015850:Interleukin-6; C118451:LFM A13; D055666:Lipopeptides; D008070:Lipopolysaccharides; D009570:Nitriles; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium