Targeted inactivation of the IL-4 receptor alpha chain I4R motif promotes allergic airway inflammation.
The insulin/interleukin-4 (IL-4) receptor (I4R) motif mediates the association of insulin receptor substrate (IRS)-2 with the interleukin-4 (IL-4)Ralpha chain and transduces mitogenic signals in response to IL-4. Its physiological functions were analyzed in mice with a germline point mutation that changed the motif's effector tyrosine residue into phenylalanine (Y500F). The Y500F mutation abrogated IRS-2 phosphorylation and impaired IL-4-induced CD4+ T lymphocyte proliferation but left unperturbed Stat6 activation, up-regulation of IL-4-responsive gene products, and Th cell differentiation under Th2 polarizing conditions. However, in vivo the Y500F mutation was associated with increased allergen-induced IgE production, airway responsiveness, tissue eosinophilia, and mucus production. These results define an important role for the I4R motif in regulating allergic inflammation.
Blaeser
Frank
F
Deparment of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Bryce
Paul J
PJ
Ho
Nga
N
Raman
Vidya
V
Dedeoglu
Fatma
F
Donaldson
Debra D
DD
Geha
Raif S
RS
Oettgen
Hans C
HC
Chatila
Talal A
TA
D000818:Animals; D007073:Immunoglobulin E; D007249:Inflammation; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009154:Mutation; D010750:Phosphoproteins; D011972:Receptor, Insulin; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000502:physiology*; D012130:Respiratory Hypersensitivity / Q000276:immunology*; D018418:Th2 Cells
D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D019948:Receptors, Interleukin-4; D007073:Immunoglobulin E; D011972:Receptor, Insulin