Negative regulation of immunoglobulin E-dependent allergic responses by Lyn kinase.
A role for Lyn kinase as a positive regulator of immunoglobulin (Ig)E-dependent allergy has long been accepted. Contrary to this belief, Lyn kinase was found to have an important role as a negative regulator of the allergic response. This became apparent from the hyperresponsive degranulation of lyn-/- bone marrow-derived mast cells, which is driven by hyperactivation of Fyn kinase that occurs, in part, through the loss of negative regulation by COOH-terminal Src kinase (Csk) and the adaptor, Csk-binding protein. This phenotype is recapitulated in vivo as young lyn-/- mice showed an enhanced anaphylactic response. In vivo studies also demonstrated that as lyn-/- mice aged, their serum IgE increased as well as occupancy of the high affinity IgE receptor (FcepsilonRI). This was mirrored by increased circulating histamine, increased mast cell numbers, increased cell surface expression of the high affinity IgE receptor (FcepsilonRI), and eosinophilia. The increased IgE production was not a consequence of increased Fyn kinase activity in lyn-/- mice because both lyn-/- and lyn-/- fyn-/- mice showed high IgE levels. Thus, lyn-/- mice and mast cells thereof show multiple allergy-associated traits, causing reconsideration of the possible efficacy in therapeutic targeting of Lyn in allergic disease.
Odom
Sandra
S
Molecular Inflammation Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Gomez
Gregorio
G
Kovarova
Martina
M
Furumoto
Yasuko
Y
Ryan
John J
JJ
Wright
Harry V
HV
Gonzalez-Espinosa
Claudia
C
Hibbs
Margaret L
ML
Harder
Kenneth W
KW
Rivera
Juan
J
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D015550:Cell Degranulation; D006632:Histamine / Q000097:blood; D006967:Hypersensitivity / Q000276:immunology*; D007073:Immunoglobulin E / Q000276:immunology*; D008407:Mast Cells / Q000201:enzymology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D017455:Receptors, IgE / Q000032:analysis; D019061:src-Family Kinases / Q000502:physiology*
D008565:Membrane Proteins; C498709:Pag1 protein, mouse; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D017455:Receptors, IgE; D007073:Immunoglobulin E; D006632:Histamine; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases