title: ERK1 is important for Th2 differentiation and development of experimental asthma.
abstract: The ERK1/2 signaling pathway regulates a variety of T-cell functions. We observed dynamic changes in the expression of ERK1/2 during T-helper cell differentiation. Specifically, the expression of ERK1/2 was decreased and increased by IL-12 and IL-4, respectively. To address this subject further, we examined the specific role of ERK1 in Th2 differentiation and development of experimental asthma using ERK1(-/-) mice. ERK1(-/-) mice were unable to mount airway inflammation and hyperreactivity in two different models of asthma, acute and chronic. ERK1(-/-) mice had reduced expression of Th2 cytokines IL-4 and IL-5 but not IL-17A or IFN-γ. They had reduced levels of allergen-specific IgE and blood eosinophils. T cells from immunized ERK1(-/-) mice manifested reduced proliferation in response to the sensitizing allergen. ERK1(-/-) T cells had reduced and short-lived expression of JunB following TCR stimulation, which likely contributed to their impaired Th2 differentiation. Immunized ERK1(-/-) mice showed reduced numbers of CD44(high) CD4 T cells in the spleen. In vitro studies demonstrated that Th2 but not Th1 cells from ERK1(-/-) mice had reduced numbers of CD44(high) cells. Finally, CD4 T cells form ERK1(-/-) mice expressed higher levels of BIM under growth factor-deprived conditions and reduced Mcl-1 on stimulation. As a result, the survival of CD4 T cells, especially CD44(high) Th2 cells, was much reduced in ERK1(-/-) mice. We conclude that ERK1 plays a nonredundant role in Th2 differentiation and development of experimental asthma. ERK1 controls Th2 differentiation and survival through its effect on JunB and BIM, respectively.
authors.affiliation: Division of Allergy and Immunology, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Goplen
authors.forename: Zunayet
authors.initials: Z
authors.lastname: Karim
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Zhuang
authors.forename: Hua
authors.initials: H
authors.lastname: Huang
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Gorska
authors.forename: Erwin
authors.initials: E
authors.lastname: Gelfand
authors.forename: Gilles
authors.initials: G
authors.lastname: Pagés
authors.forename: Jacques
authors.initials: J
authors.lastname: Pouysségur
authors.forename: Rafeul
authors.initials: R
authors.lastname: Alam
mesh_terms: D000818:Animals; D001249:Asthma / Q000201:enzymology / Q000473:pathology*; D018791:CD4 Lymphocyte Count; D002454:Cell Differentiation; D049109:Cell Proliferation; D004804:Eosinophils / Q000166:cytology; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology*
chemical_list: D048052:Mitogen-Activated Protein Kinase 3