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Infection of humans with Ehrlichia chaffeensis, the etiologic agent of human monocytic ehrlichiosis, can cause hepatitis of various levels of severity. When the three human isolates of E. chaffeensis, each belonging to a different genogroup, are inoculated into severe combined immunodeficiency mice, the order of severity of clinical signs and bacterial burden detected in the liver is as follows (from greatest to least severity and highest to lowest burden): strain Wakulla, followed by strain Liberty, followed by strain Arkansas. In this article, we used microarray analysis to define transcriptional profiles characteristic of the histopathological features in the mouse liver. Cytokine and chemokine profiles and their receptor profiles were strikingly different among the three strains of E. chaffeensis: gamma interferon, CCL5, CXCL1, CXCL2, CXCL7, CXCL9, interleukin 2 receptor gamma (IL2R␥), IL21R, CCR2, and CXCR6 were highly upregulated with strain Arkansas; and tumor necrosis factor (TNF), CCL2, CCL3, CCL5, CCL6, CCL12, CCL20, CXCL2, CXCL7, CXCL9, CXCL13, TNF receptor superfamily 9 (TNFRSF9), TNFRSF13, IL1R2, IL2R␥, IL20R, IL21R, CCR1, CCR2, and CXCR4 were highly upregulated with strain Wakulla. With strain Liberty, only CXCL13 was highly upregulated, and IL13R␣2 was downregulated. In livers infected with the Arkansas strain, monocytes/macrophages and NK cells were enriched in the granulomas and an increase in NK cell marker mRNAs was detected. Livers infected with the Wakulla strain displayed infiltration of significantly more neutrophils and an increase in neutrophil marker mRNAs. Genes commonly upregulated in liver tissue infected with the three strains are other host innate immune and inflammatory response genes, including those encoding several acute-phase proteins. Genes downregulated commonly are related to host physiologic functions. The results suggest that marked modulation of host cytokine and chemokine profiles by E. chaffeensis strains underlies the distinct host liver disease.Human monocytic ehrlichiosis (HME) was discovered in 1986 (34), and the etiologic agent, a monocyte-tropic Ehrlichia species, was isolated several years later and named Ehrlichia chaffeensis (15). HME is one of the most prevalent life-threatening tick-borne zoonoses in North America and was designated a nationally notifiable disease in 1998 (35). HME is an acute febrile illness characterized by headache, malaise, nausea, and myalgia and/or arthralgia and frequently accompanied by leukopenia, thrombocytopenia, anemia, and elevation of hepatic transaminase levels (43). The severity of HME, however, varies from subclinical infection to death. A previous investigation of the pathology of injury in liver tissues from five immunocompetent patients, one human immunodeficiency virus (HIV)-infected patient, and one monoclonal gammopathy patient with laboratory-confirmed HME revealed scattered lobular lymphohistiocytic foci and diffuse lymphohistiocytic infiltration and Kupffer cell hyperplasia with moderate cholestasis (cholestasis w...
Infection of humans with Ehrlichia chaffeensis, the etiologic agent of human monocytic ehrlichiosis, can cause hepatitis of various levels of severity. When the three human isolates of E. chaffeensis, each belonging to a different genogroup, are inoculated into severe combined immunodeficiency mice, the order of severity of clinical signs and bacterial burden detected in the liver is as follows (from greatest to least severity and highest to lowest burden): strain Wakulla, followed by strain Liberty, followed by strain Arkansas. In this article, we used microarray analysis to define transcriptional profiles characteristic of the histopathological features in the mouse liver. Cytokine and chemokine profiles and their receptor profiles were strikingly different among the three strains of E. chaffeensis: gamma interferon, CCL5, CXCL1, CXCL2, CXCL7, CXCL9, interleukin 2 receptor gamma (IL2R␥), IL21R, CCR2, and CXCR6 were highly upregulated with strain Arkansas; and tumor necrosis factor (TNF), CCL2, CCL3, CCL5, CCL6, CCL12, CCL20, CXCL2, CXCL7, CXCL9, CXCL13, TNF receptor superfamily 9 (TNFRSF9), TNFRSF13, IL1R2, IL2R␥, IL20R, IL21R, CCR1, CCR2, and CXCR4 were highly upregulated with strain Wakulla. With strain Liberty, only CXCL13 was highly upregulated, and IL13R␣2 was downregulated. In livers infected with the Arkansas strain, monocytes/macrophages and NK cells were enriched in the granulomas and an increase in NK cell marker mRNAs was detected. Livers infected with the Wakulla strain displayed infiltration of significantly more neutrophils and an increase in neutrophil marker mRNAs. Genes commonly upregulated in liver tissue infected with the three strains are other host innate immune and inflammatory response genes, including those encoding several acute-phase proteins. Genes downregulated commonly are related to host physiologic functions. The results suggest that marked modulation of host cytokine and chemokine profiles by E. chaffeensis strains underlies the distinct host liver disease.Human monocytic ehrlichiosis (HME) was discovered in 1986 (34), and the etiologic agent, a monocyte-tropic Ehrlichia species, was isolated several years later and named Ehrlichia chaffeensis (15). HME is one of the most prevalent life-threatening tick-borne zoonoses in North America and was designated a nationally notifiable disease in 1998 (35). HME is an acute febrile illness characterized by headache, malaise, nausea, and myalgia and/or arthralgia and frequently accompanied by leukopenia, thrombocytopenia, anemia, and elevation of hepatic transaminase levels (43). The severity of HME, however, varies from subclinical infection to death. A previous investigation of the pathology of injury in liver tissues from five immunocompetent patients, one human immunodeficiency virus (HIV)-infected patient, and one monoclonal gammopathy patient with laboratory-confirmed HME revealed scattered lobular lymphohistiocytic foci and diffuse lymphohistiocytic infiltration and Kupffer cell hyperplasia with moderate cholestasis (cholestasis w...
We show that TTA has the ability to attenuate tumor necrosis factor alpha-mediated endothelial cell activation, further supporting antiinflammatory effects of this fatty acid, possibly involving both PPAR-alpha-dependent and -independent pathways.
Objective-Tumor necrosis factor ␣ (TNF-␣), a key proinflammatory cytokine acting on the endothelium, activates endothelial nitric oxide synthase (eNOS). We have examined the signaling pathway leading to this activation and its biological role in endothelium, which are still unknown. Methods and Results-In human endothelial cells, we found that eNOS activation by TNF-␣ is time dependent and requires activation of Akt, a known eNOS activator. eNOS activation was preceded by sequential activation of neutral-sphingomyelinase-2 (N-SMase2) and sphingosine-kinase-1 (SK1) and generation of sphingosine-1-phosphate (Sph1P). Inhibition of N-SMase2 inhibited Sph1P formation, whereas inhibition of SK1 did not affect N-SMase2 activation by TNF-␣. Blockade of N-SMase2, SK1, or the Sph1P receptors S1P 1 and S1P 3 , either by silencing or pharmacological inhibitors, prevented eNOS activation. Thus, eNOS is activated by TNF-␣ via S1P receptors, activated by Sph1P generated through N-SMase2 and SK1 activation. We found that nitric oxide generated through this pathway has a biological role, because it inhibits the expression of E-selectin and the adhesion of dendritic cells to the endothelium stimulated by TNF-␣. Key Words: endothelial NO synthase Ⅲ TNF-␣ Ⅲ neutral sphingomyelinase 2 Ⅲ sphingosine kinase 1 Ⅲ sphingosine 1 phosphate N itric oxide (NO) generated in the endothelium by the endothelial NO synthase (eNOS) plays crucial roles not only in physiology but also in regulating specific inflammatory events involving the endothelium, such as the expression of adhesion molecules and leukocyte adhesion. 1,2 Indeed, eNOS Ϫ/Ϫ animals, when exposed to inflammatory stimuli, display significant increases in extravasated neutrophils and poor wound healing and are more prone to diseases in which inflammation is significant, including atherosclerosis and diabetes. 1,2 eNOS regulates the effects on migration, angiogenesis, vasodilation, endothelial barrier permeability, apoptosis, and expression of inflammatory and adhesion molecules exerted by tumor necrosis factor ␣ (TNF-␣), a key proinflammatory cytokine acting on the endothelium. [3][4][5][6][7][8][9] In some cases, the effects of NO appeared directly associated with eNOS activity; 8,9 in others, they were consistent with the involvement of this enzyme, because they were too rapid to be explained by synthesis of the inducible NO synthase (NOS) 1,2 or because they took place in human cells 4,7 that do not express inducible NOS when exposed to TNF-␣ alone. 8,10 Despite the relevance to TNF-␣ action, eNOS activation by the cytokine in endothelial cells had been investigated in only 2 studies 8,11 that did not provide evidence of the pathway involved, apart from the identification of a phosphatidylinositol 3-kinase (PI3K)/Aktdependent step, 11 a signaling event common to many eNOSactivating stimuli. 2 In a recent study in HeLa cells, we reported that eNOS activation by TNF-␣ is mediated by the activation of neutral sphingomyelinase (N-SMase), with generation of the sphingolipid ceramid...
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