The Ets2 transcription factor is constitutively phosphorylated on residue Thr(72) 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 Thr(72) of Ets2 during inflammation, the Ets2(A72) mutant allele, which cannot be phosphorylated on Thr(72), was combined with the Hcph(me-v) allele in mice. Ets2(A72/A72) moderated the inflammation-related pathology of Hcph(me-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 Ets2(A72/A72) allele resulted in decreased expression of inflammatory response genes, including TNF-alpha, CCL3, matrix metalloprotease 9, integrin alpha(M), and Bcl-X in alveolar macrophage. Ets2 phosphorylation was required for persistent activation of TNF-alpha 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.