Limits...
Role of Fas/FasL in regulation of inflammation in vaginal tissue during HSV-2 infection.

Krzyzowska M, Shestakov A, Eriksson K, Chiodi F - Cell Death Dis (2011)

Bottom Line: Despite upregulation of Fas and FasL, HSV-2-infected keratinocytes and epithelial cells showed a moderate level of apoptosis due to upregulated expression of the anti-apoptotic factors Bcl-2, Akt kinase and NF-κB.Inflammatory lesions within the HSV-2-infected epithelium of C57BL6 mice consisted of infected cells upregulating Fas, FasL and Bcl-2, uninfected cells upregulating Fas and neutrophils expressing both Fas and FasL.We conclude that the Fas pathway participates in regulation of inflammatory response in the vaginal epithelium at the initial stage of HSV-2 infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. krzyzowskam@yahoo.com

ABSTRACT
To assess the role of Fas in lesion development during genital HSV-2 infection, we used a well-established HSV-2 murine model applied to MRL-Fas(lpr)/J (Fas-/-) and C3-Fasl(gld)/J (FasL-/-) C57BL6 mice. In vitro infection of murine keratinocytes and epithelial cells was used to clarify molecular details of HSV-2 infection. Despite upregulation of Fas and FasL, HSV-2-infected keratinocytes and epithelial cells showed a moderate level of apoptosis due to upregulated expression of the anti-apoptotic factors Bcl-2, Akt kinase and NF-κB. Inflammatory lesions within the HSV-2-infected epithelium of C57BL6 mice consisted of infected cells upregulating Fas, FasL and Bcl-2, uninfected cells upregulating Fas and neutrophils expressing both Fas and FasL. Apoptosis was detected in HSV-2-infected cells and to even higher extent in non-infected cells surrounding HSV-2 infection sites. HSV-2 infection of Fas- and FasL-deficient mice led to increased apoptosis and stronger recruitment of neutrophils within the infection sites. We conclude that the Fas pathway participates in regulation of inflammatory response in the vaginal epithelium at the initial stage of HSV-2 infection.

Show MeSH

Related in: MedlinePlus

Schematic model on the role of Fas/FasL pathway in regulation of local inflammation during HSV-2 infection of epithelium. Upon stimulation by FasL-expressing cells, Fas-expressing cells respond by producing proinflammatory cytokines. Autocrine upregulation of FasL by epithelial cells, however, appears to block the effects of extrinsic Fas stimulation. HSV-2 infected cells, although upregulating Fas and FasL expression gain an apoptosis resistant status due to upregulation of anti-apoptotic proteins (Bcl-2, NF-κB, Akt kinase)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3101811&req=5

fig8: Schematic model on the role of Fas/FasL pathway in regulation of local inflammation during HSV-2 infection of epithelium. Upon stimulation by FasL-expressing cells, Fas-expressing cells respond by producing proinflammatory cytokines. Autocrine upregulation of FasL by epithelial cells, however, appears to block the effects of extrinsic Fas stimulation. HSV-2 infected cells, although upregulating Fas and FasL expression gain an apoptosis resistant status due to upregulation of anti-apoptotic proteins (Bcl-2, NF-κB, Akt kinase)

Mentions: It was previously shown30 that human epithelial HEp-2 cells infected with HSV-1 were resistant to Fas-induced apoptosis. In our study, HSV-2-infected murine epithelial cells and keratinocytes upregulated Fas and FasL. This event should render the HSV-2-infected cells sensitive to apoptosis delivered either by FasL present on neighboring cells or through an autocrine pathway (Figure 8). However, a closer analysis showed that induction of apoptosis in the infected epithelial and keratinocytes cultures by a cytotoxic Fas antibody involved a large portion of uninfected cells, which also upregulated Fas, therefore leading to a decrease in the number of potential target cells for HSV-2 infection; this process could be diverted by the addition of FasL blocking antibody. These results show that HSV-2-infected cells are relatively resistant to Fas-induced apoptosis and that cell death of these cells likely occurs through other pathways. Fleck et al.4 also showed that, although murine macrophages upregulated Fas and TNFR1 receptors upon HSV-2 infection, inhibition of Fas by addition of soluble Fas and blocking of TNF-α did not prevent HSV-2-induced apoptosis. In the human T-cell line Jurkat, HSV-2 induced apoptosis through extrinsic (death receptors) and intrinsic (mitochondrial) pathways.31 Therefore, it is likely that mitochondrial pathway may also be involved in apoptosis during HSV-2 infection of epithelial cells and keratinocytes.


Role of Fas/FasL in regulation of inflammation in vaginal tissue during HSV-2 infection.

Krzyzowska M, Shestakov A, Eriksson K, Chiodi F - Cell Death Dis (2011)

Schematic model on the role of Fas/FasL pathway in regulation of local inflammation during HSV-2 infection of epithelium. Upon stimulation by FasL-expressing cells, Fas-expressing cells respond by producing proinflammatory cytokines. Autocrine upregulation of FasL by epithelial cells, however, appears to block the effects of extrinsic Fas stimulation. HSV-2 infected cells, although upregulating Fas and FasL expression gain an apoptosis resistant status due to upregulation of anti-apoptotic proteins (Bcl-2, NF-κB, Akt kinase)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3101811&req=5

fig8: Schematic model on the role of Fas/FasL pathway in regulation of local inflammation during HSV-2 infection of epithelium. Upon stimulation by FasL-expressing cells, Fas-expressing cells respond by producing proinflammatory cytokines. Autocrine upregulation of FasL by epithelial cells, however, appears to block the effects of extrinsic Fas stimulation. HSV-2 infected cells, although upregulating Fas and FasL expression gain an apoptosis resistant status due to upregulation of anti-apoptotic proteins (Bcl-2, NF-κB, Akt kinase)
Mentions: It was previously shown30 that human epithelial HEp-2 cells infected with HSV-1 were resistant to Fas-induced apoptosis. In our study, HSV-2-infected murine epithelial cells and keratinocytes upregulated Fas and FasL. This event should render the HSV-2-infected cells sensitive to apoptosis delivered either by FasL present on neighboring cells or through an autocrine pathway (Figure 8). However, a closer analysis showed that induction of apoptosis in the infected epithelial and keratinocytes cultures by a cytotoxic Fas antibody involved a large portion of uninfected cells, which also upregulated Fas, therefore leading to a decrease in the number of potential target cells for HSV-2 infection; this process could be diverted by the addition of FasL blocking antibody. These results show that HSV-2-infected cells are relatively resistant to Fas-induced apoptosis and that cell death of these cells likely occurs through other pathways. Fleck et al.4 also showed that, although murine macrophages upregulated Fas and TNFR1 receptors upon HSV-2 infection, inhibition of Fas by addition of soluble Fas and blocking of TNF-α did not prevent HSV-2-induced apoptosis. In the human T-cell line Jurkat, HSV-2 induced apoptosis through extrinsic (death receptors) and intrinsic (mitochondrial) pathways.31 Therefore, it is likely that mitochondrial pathway may also be involved in apoptosis during HSV-2 infection of epithelial cells and keratinocytes.

Bottom Line: Despite upregulation of Fas and FasL, HSV-2-infected keratinocytes and epithelial cells showed a moderate level of apoptosis due to upregulated expression of the anti-apoptotic factors Bcl-2, Akt kinase and NF-κB.Inflammatory lesions within the HSV-2-infected epithelium of C57BL6 mice consisted of infected cells upregulating Fas, FasL and Bcl-2, uninfected cells upregulating Fas and neutrophils expressing both Fas and FasL.We conclude that the Fas pathway participates in regulation of inflammatory response in the vaginal epithelium at the initial stage of HSV-2 infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. krzyzowskam@yahoo.com

ABSTRACT
To assess the role of Fas in lesion development during genital HSV-2 infection, we used a well-established HSV-2 murine model applied to MRL-Fas(lpr)/J (Fas-/-) and C3-Fasl(gld)/J (FasL-/-) C57BL6 mice. In vitro infection of murine keratinocytes and epithelial cells was used to clarify molecular details of HSV-2 infection. Despite upregulation of Fas and FasL, HSV-2-infected keratinocytes and epithelial cells showed a moderate level of apoptosis due to upregulated expression of the anti-apoptotic factors Bcl-2, Akt kinase and NF-κB. Inflammatory lesions within the HSV-2-infected epithelium of C57BL6 mice consisted of infected cells upregulating Fas, FasL and Bcl-2, uninfected cells upregulating Fas and neutrophils expressing both Fas and FasL. Apoptosis was detected in HSV-2-infected cells and to even higher extent in non-infected cells surrounding HSV-2 infection sites. HSV-2 infection of Fas- and FasL-deficient mice led to increased apoptosis and stronger recruitment of neutrophils within the infection sites. We conclude that the Fas pathway participates in regulation of inflammatory response in the vaginal epithelium at the initial stage of HSV-2 infection.

Show MeSH
Related in: MedlinePlus