src homology 2 domain-containing tyrosine phosphatase SHP-1 controls the development of allergic airway inflammation.
Th2 cells are generated from naive CD4 T cells upon T cell receptor (TCR) recognition of antigen and IL-4 stimulation and play crucial roles in humoral immunity against infectious microorganisms and the pathogenesis of allergic and autoimmune diseases. A tyrosine phosphatase, SHP-1, that contains src homology 2 (SH2) domains is recognized as a negative regulator for various intracellular signaling molecules, including those downstream of the TCR and the IL-4 receptor. Here we assessed the role of SHP-1 in Th1/Th2 cell differentiation and in the development of Th2-dependent allergic airway inflammation by using a natural SHP-1 mutant, the motheaten mouse. CD4 T cells appear to develop normally in the heterozygous motheaten (me/+) thymus even though they express decreased amounts of SHP-1 (about one-third the level of wild-type thymus). The me/+ naive splenic CD4 T cells showed enhanced activation by IL-4 receptor-mediated signaling but only marginal enhancement of TCR-mediated signaling. Interestingly, the generation of Th2 cells was increased and specific cytokine production of mast cells was enhanced in me/+ mice. In an OVA-induced allergic airway inflammation model, eosinophilic inflammation, mucus hyperproduction, and airway hyperresponsiveness were enhanced in me/+ mice. Thus, SHP-1 may have a role as a negative regulator in the development of allergic responses, such as allergic asthma.
Kamata
Tohru
T
Department of Molecular Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Yamashita
Masakatsu
M
Kimura
Motoko
M
Murata
Kaoru
K
Inami
Masamichi
M
Shimizu
Chiori
C
Sugaya
Kaoru
K
Wang
Chrong-Reen
CR
Taniguchi
Masaru
M
Nakayama
Toshinori
T
D000818:Animals; D001249:Asthma / Q000378:metabolism; D001980:Bronchi / Q000276:immunology* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D004804:Eosinophils / Q000276:immunology; D005434:Flow Cytometry; D006579:Heterozygote; D006967:Hypersensitivity / Q000276:immunology*; D015151:Immunoblotting; D007249:Inflammation; D018793:Interleukin-13 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008407:Mast Cells / Q000166:cytology; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D008856:Microscopy, Fluorescence; D009154:Mutation; D010641:Phenotype; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D019948:Receptors, Interleukin-4 / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D013997:Time Factors; D018909:src Homology Domains
D003432:Cross-Linking Reagents; D018793:Interleukin-13; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D019948:Receptors, Interleukin-4; D016210:Methacholine Chloride; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse