YOPJ OF YERSINIA-PSEUDOTUBERCULOSIS IS REQUIRED FOR THE INHIBITION OFMACROPHAGE TNF-ALPHA PRODUCTION AND DOWN-REGULATION OF THE MAP KINASES P38 AND JNK
Le. Palmer et al., YOPJ OF YERSINIA-PSEUDOTUBERCULOSIS IS REQUIRED FOR THE INHIBITION OFMACROPHAGE TNF-ALPHA PRODUCTION AND DOWN-REGULATION OF THE MAP KINASES P38 AND JNK, Molecular microbiology, 27(5), 1998, pp. 953-965
Exposure of macrophages to lipopolysaccharide (LPS) leads to productio
n of the pro-inflammatory cytokine, tumour necrosis factor alpha (TNF-
alpha). Previous studies have suggested that pathogenic Yersinia spp.
inhibit LPS-mediated production of TNF-alpha in macrophages, and that
one of the Yop proteins secreted by the plasmid-encoded type III pathw
ay is required for this activity. We found that TNF-alpha production w
as inhibited when J774A.1 murine macrophages were infected with wild-t
ype Y. pseudotuberculosis but not with an isogenic ysc mutant defectiv
e for Yop secretion. We inactivated multiple yop genes to identify whi
ch of these factors are required for the inhibition of TNF-alpha produ
ction. A mutant unable to express yopJ was defective for the inhibitio
n of TNF-alpha production. Production of TNF-alpha is regulated at the
transcriptional and translational levels by several mitogen-activated
protein (MAP) kinases. The MAP kinases p38 and JNK underwent sustaine
d 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 JN
K and to inhibit production of TNF-alpha was restored by the expressio
n of yopJ(+) in trans. Therefore, YopJ is required for Y. pseudotuberc
ulosis to downregulate MAP kinases and inhibit the production of TNF-a
lpha in macrophages.