Delayed Hepatocellular Mitotic Progression and Impaired Liver Regeneration in Early Growth Response-1-deficient Mice

ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen that is a common cause of nosocomial infections. The molecular mechanisms governing immune responses to P. aeruginosa infection remain incompletely defined. Early growth response 1 (Egr-1) is a zinc-finger transcription factor that controls inflammatory responses. Here, we characterized the role of Egr-1 in host defense against P. aeruginosa infection in a mouse model of acute bacterial pneumonia. Egr-1 expression was rapidly and transiently induced in response to P. aeruginosa infection. Egr-1-deficient mice displayed decreased mortality, reduced levels of proinflammatory cytokines (tumor necrosis factor [TNF], interleukin-1β [IL-1β], IL-6, IL-12, and IL-17), and enhanced bacterial clearance from the lung. Egr-1 deficiency caused diminished NF-κB activation in P. aeruginosa-infected macrophages independently of IκBα phosphorylation. A physical interaction between Egr-1 and NF-κB p65 was found in P. aeruginosa-infected macrophages, suggesting that Egr-1 could be required for assembly of heterodimeric transcription factors that direct synthesis of inflammatory mediators. Interestingly, Egr-1 deficiency had no impact on neutrophil recruitment in vivo due to its differential effects on chemokine production, which included diminished accumulation of KC (CXCL1), MIP2 (CXCL2), and IP-10 (CXCL10) and increased accumulation of LIX (CXCL5). Importantly, Egr-1-deficient macrophages and neutrophils displayed significant increases in nitric oxide production and bacterial killing ability that correlated with enhanced bacterial clearance in Egr-1-deficient mice. Together, these findings suggest that Egr-1 plays a detrimental role in host defense against P. aeruginosa acute lung infection by promoting systemic inflammation and negatively regulating the nitric oxide production that normally assists with bacterial clearance.

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Altered molecular response to adrenoreceptor-induced cardiac hypertrophy in Egr-1-deficient mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.278.3.h796 ◽

2000 ◽

Vol 278 (3) ◽

pp. H796-H805 ◽

Cited By ~ 39

Author(s):

Nacéra Saadane ◽

Lesley Alpert ◽

Lorraine E. Chalifour

Keyword(s):

Gene Expression ◽

Atrial Natriuretic Factor ◽

Growth Response ◽

Early Growth ◽

Heart Weight ◽

Molecular Response ◽

Early Growth Response ◽

Increased Sensitivity ◽

Early Growth Response 1 ◽

Deficient Mice

Unmanipulated early growth response-1 (Egr-1)-deficient −/− mice have similar heart-to-body weight ratios but express lower amounts of atrial natriuretic factor (ANF), β-myosin heavy chain (β-MHC), skeletal actin, NGF1-A binding protein (NAB)-2, Sp1, c- fos, c- jun, GATA-4, and Nkx2.5 than +/+ or +/− mice. α-MHC, tubulin, and NAB-1 expression was similar. Isoproterenol (Iso) and phenylephrine (PE) infusion into +/+ and −/− mice increased heart weight, ANF, β-MHC, skeletal actin, Sp1, NAB-2, c- fos, and c- jun expression, but induction in −/− mice was lower. Only Iso + PE-treated +/+ mice showed induction of NAB-1, GATA-4, and Nkx2.5. Foci of fibrosis were found in Iso + PE-treated −/− and +/+ mice. Surprisingly, vehicle-treated −/− mice displayed fibrosis and increased Sp1, skeletal actin, Nkx2.5, and GATA-4 expression without hypertrophy. Minipump removal caused the agonist-treated hearts and gene expression to regress to control or near-control levels. Thus Egr-1 deficiency caused a blunted catecholamine-induced hypertrophy response and increased sensitivity to stress.

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