Protein Kinase A-Mediated Inhibition of Gamma Interferon-Induced Tyrosine Phosphorylation of Janus Kinases and Latent Cytoplasmic Transcription Factors in Human Monocytes by<i>Ehrlichia chaffeensis</i>

Lee, Eunjoo H.; Rikihisa, Yasuko

doi:10.1128/iai.66.6.2514-2520.1998

Cited by 69 publications

(22 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…An inhibitory effect on IFN‐γ‐induced Stat‐1 phosphorylation has been reported in Ehrlichia chaffeensis ‐infected human monocytes, but the mechanism is certainly different from theone described in this investigation as the effect was immediate and did not require phagocytosis 17.…”

Section: Discussioncontrasting

confidence: 67%

Block of Stat-1 activation in macrophages phagocytosing bacteria causes reduced transcription of CIITA and consequent impaired antigen presentation

et al. 2002

View full text Add to dashboard Cite

The IFN‐γ‐induced HLA class II expression in human macrophages was drastically reduced after phagocytosis of Escherichia coli. HLA class II down‐modulation depended on phagocytosis of bacteria and could not be reproduced by phagocytosis of inert particles or by treatment with lipopolysaccharide. Study of the kinetics and molecular analysis showed that class II molecules and corresponding mRNA were up‐regulated at 6 h after phagocytosis of bacteria. Subsequently, a progressive reduction of mRNA occurred, and, at 72 h, as little as 25% of the class II mRNA level of IFN‐γ‐treated control cells was found. This was due to reduced transcription of the class II transcriptional activator CIITA, as a consequence of reduced immediate‐early inducible factor (IRF‐1) and particularly of reduced phosphorylated Stat‐1 homodimers, nuclear factors both necessary for optimal triggering of the CIITA promoter. Failure to sustain IFN‐γ‐induced CIITA up‐modulation during phagocytosis of bacteria had functional implications, as human macrophages could not adequately process and present antigenic peptides to HLA‐DR‐restricted antigen‐specific T cells. This is the first evidence that phagocytosis of bacteria can down‐modulate HLA class II expression in normal human macrophages by acting at the level of expression of CIITA.

show abstract

Section: Discussioncontrasting

confidence: 67%

Block of Stat-1 activation in macrophages phagocytosing bacteria causes reduced transcription of CIITA and consequent impaired antigen presentation

et al. 2002

View full text Add to dashboard Cite

show abstract

“…As the downregulation of mRNA expressions of TLR2/4 and CD14 requires live E. chaffeensis, the unidentified effector of the type IV secretion system may have a role in such inhibition. Alternatively, PKA activation induced by E. chaffeensis (Lee and Rikihisa, 1998) may be involved in the downregulation, because the activation of ERK1/2 and p38 MAPK is mainly mediated by Ras/Raf-1/MEK and MKK3/6, respectively, both of which can be inhibited by PKA-mediated phosphorylation of Raf-1 (Cook and McCormick, 1993;Tamir et al, 1996;Dumaz and Marais, 2003;Schorey and Cooper, 2003).…”

Section: Discussionmentioning

confidence: 99%

Ehrlichia chaffeensisdownregulates surface Toll-like receptors 2/4, CD14 and transcription factors PU.1 and inhibits lipopolysaccharide activation of NF-κB, ERK 1/2 and p38 MAPK in host monocytes

Lin

Rikihisa²

2004

Cellular Microbiology

Self Cite

View full text Add to dashboard Cite

SummaryMicrobial ligands, such as lipopolysaccharide (LPS), activate Toll-like receptors (TLRs) of mononuclear phagocytes, thus activating transcription factors including NF-k k k k B and inducing antimicrobial activity. Ehrlichia chaffeensis , an obligatory intramonocytic Gram-negative bacterium, causes human monocytic ehrlichiosis. In the present study, we found that E. chaffeensis-infected human monocytes became progressively less responsive to Escherichia coli lipopolysaccharide (LPS) in activating NF-k k k k B and mobilizing ehrlichiacidal activities. E. chaffeensis infection caused downregulation of the expression of several pattern recognition receptors, such as CD14, TLR2 and TLR4, as revealed by flow cytometry and/or reverse transcription polymerase chain reaction analysis. Electrophoretic mobility shift assay revealed that the activity of a transcription factor PU.1 was also downregulated by E. chaffeensis infection. ERK 1/2 and p38 MAPK were slightly activated at the early stage of E. chaffeensis infection; however, the activations of ERK 1/2 and p38 MAPK by LPS treatment were subsequently reduced in E. chaffeensis -infected monocytes compared with those in uninfected monocytes. Like E. chaffeensis , the p38 MAPK-specific inhibitor SB 203580 downregulated PU.1 activity and the expression of TLR2, TLR4 and CD14 in human monocytes, suggesting that the inhibition of p38 MAPK by E. chaffeensis is involved in the suppression of several downstream signalling pathways. These data point to a novel mechanism by which E. chaffeensis can survive by inhibiting critical signalling in monocyte activation pathways linked to pattern recognition receptors.

show abstract

“…A. phagocytophilum impairs IFN-g signaling in infected neutrophils, including inhibiting IP-10/CXCL10 and MIG/CXCL9 expression, IFN-g receptor a-chain CD119, and phosphorylated Stat1, as well as other factors that promote intracellular survival (3). Likewise, the related Ehrlichia chaffeensis infection of THP-1 monocytes blocks phosphorylation of Stat1, JAK1 and JAK2, suggesting that these agents have broad activity that directly targets infected host cells (22). The current observations differ because most of the ex vivo splenocytes we examined were neither infected nor potential hosts for A. phagocytophilum.…”

Section: Discussionmentioning

confidence: 99%

Anaplasma phagocytophilum, interferon gamma production and Stat1 signaling

Choi

Dumler

2013

Microbiology and Immunology

View full text Add to dashboard Cite

Human granulocytic anaplasmosis (HGA) is caused by the obligate intracellular bacterium, Anaplasma phagocytophilum. The proinflammatory cytokine, IFN-γ is necessary for innate immunity and plays an important role in the induction of severe histopathology in A. phagocytophilum-infected mice and disease in horses and humans. In this study, we examined the role of activation of signal transducer and activator of transcription (Stat) 1 phosphorylation with A. phagocytophilum infection, and found it to be markedly increased at day 7 post infection compared to mock-infected controls. This increase in phosphorylated Stat1 (pStat1) was significantly correlated with IFN-γ production and inflammatory tissue injury. Since pStat1 operates as a transcription factor central to the generation of effectors of inflammatory injury, these data suggest that Stat1 signaling is involved in IFN-γ-mediated immunopathologic lesions and disease in A. phagocytophilum infection and could be an important target for intervention of disease.

show abstract

Protein Kinase A-Mediated Inhibition of Gamma Interferon-Induced Tyrosine Phosphorylation of Janus Kinases and Latent Cytoplasmic Transcription Factors in Human Monocytes byEhrlichia chaffeensis

Cited by 69 publications

References 38 publications

Block of Stat-1 activation in macrophages phagocytosing bacteria causes reduced transcription of CIITA and consequent impaired antigen presentation

Block of Stat-1 activation in macrophages phagocytosing bacteria causes reduced transcription of CIITA and consequent impaired antigen presentation

Ehrlichia chaffeensisdownregulates surface Toll-like receptors 2/4, CD14 and transcription factors PU.1 and inhibits lipopolysaccharide activation of NF-κB, ERK 1/2 and p38 MAPK in host monocytes

Anaplasma phagocytophilum, interferon gamma production and Stat1 signaling

Contact Info

Product

Resources

About