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Exposure of macrophages to lipopolysaccharide (LPS) leads to production of the pro-inflammatory cytokine, tumour necrosis factor alpha (TNF-α). Previous studies have suggested that pathogenic Yersinia spp. inhibit LPS-mediated production of TNF-α in macrophages, and that one of the Yop proteins secreted by the plasmid-encoded type III pathway is required for this activity. We found that TNF-α production was inhibited when J774A.1 murine macrophages were infected with wild-type Y. pseudotuberculosis but not with an isogenic ysc mutant defective for Yop secretion. We inactivated multiple yop genes to identify which of these factors are required for the inhibition of TNF-α production. A mutant unable to express yopJ was defective for the inhibition of TNF-α production. Production of TNF-α is regulated at the transcriptional and translational levels by several mitogen-activated protein (MAP) kinases. The MAP kinases p38 and JNK underwent sustained activation in macrophages infected with the yopJ mutant. Conversely, p38 and JNK were downregulated in macrophages infected with the wild-type strain. The ability of the yopJ mutant to downregulate p38 and JNK and to inhibit production of TNF-α was restored by the expression of yopJ+in trans. Therefore, YopJ is required for Y. pseudotuberculosis to downregulate MAP kinases and inhibit the production of TNF-α in macrophages.