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 IL17A 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.—Goplen, N., Karim, Z., Guo, L., Zhuang, Y., Huang, H., Gorska, M. M., Gelfand, E., Pagés, G., Pouysségur, J., Alam, R. ERK1 is important for Th2 differentiation and development of experimental asthma. FASEB J. 26, 1934-1945 (2012). www.fasebj.org