Activated Ets2 Is Required for Persistent Inflammatory Responses in the Motheaten Viable Model

Abstract

The Ets2 transcription factor is constitutively phosphorylated on residue Thr72 in macrophages derived from mice homozygous for the motheaten viable (me-v) allele of the hemopoietic cell phosphatase (Hcph) gene. To genetically test the importance of signaling through residue Thr72 of Ets2 during inflammation, the Ets2A72 mutant allele, which cannot be phosphorylated on Thr72, was combined with the Hcphme-v allele in mice. Ets2A72/A72 moderated the inflammation-related pathology of Hcphme-v/me-v mice, as demonstrated by the increased life span and the decreased macrophage infiltration in skin and lungs of these mice. Macrophage apoptosis induced by cytokine withdrawal was also increased in the double-mutant mice. Importantly, the Ets2A72/A72 allele resulted in decreased expression of inflammatory response genes, including TNF-α, CCL3, matrix metalloprotease 9, integrin αM, and Bcl-X in alveolar macrophage. Ets2 phosphorylation was required for persistent activation of TNF-α following LPS stimulation of bone marrow-derived macrophages. The phosphorylation of Ets2 functions in the severe inflammatory phenotype of the me-v model by mediating both macrophage survival and inflammatory gene expression.