src homology 2 domain–containing tyrosine phosphatase SHP-1 controls the development of allergic airway inflammation
Tohru Kamata, … , Masaru Taniguchi, Toshinori Nakayama
Tohru Kamata, … , Masaru Taniguchi, Toshinori Nakayama
Published January 1, 2003
Citation Information: J Clin Invest. 2003;111(1):109-119. https://doi.org/10.1172/JCI15719.
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src homology 2 domain–containing tyrosine phosphatase SHP-1 controls the development of allergic airway inflammation

Abstract

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.

Authors

Tohru Kamata, Masakatsu Yamashita, Motoko Kimura, Kaoru Murata, Masamichi Inami, Chiori Shimizu, Kaoru Sugaya, Chrong-Reen Wang, Masaru Taniguchi, Toshinori Nakayama

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OVA-induced airway hyperresponsiveness in me/+ mice. (a) Eight-week-old ...
OVA-induced airway hyperresponsiveness in me/+ mice. (a) Eight-week-old me/+ mice sensitized with OVA were subjected to OVA inhalation on days 14 and 16. One day after the last OVA inhalation, airway hyperresponsiveness in response to increasing doses of methacholine was measured in a whole-body plethysmograph. Mean values of the percent above base line are shown with SDs for four mice. A total of four independent experiments were performed with similar results. P > 0.5 for methacholine stimulation (1 mg/ml and 3 mg/ml), and P < 0.05 for methacholine stimulation (10 mg/ml and 30 mg/ml), by Student t test. (b) Eight-week-old me/+ mice were treated intraperitoneally with PBS, alum, or OVA-alum. Half of the mice with OVA-alum immunization were subjected to OVA aerosol on days 14 and 16. On day 17, methacholine-induced airway hyperresponsiveness was measured. Mean values of the percent above base line are shown for a mouse in each group. Two sets of experiments were done with similar results. penh, enhanced pause. inh., inhalation.