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Fas/FasL pathway participates in regulation of antiviral and inflammatory response during mousepox infection of lungs.

Bień K, Sokołowska J, Bąska P, Nowak Z, Stankiewicz W, Krzyzowska M - Mediators Inflamm. (2015)

Bottom Line: The lungs of ECTV-infected Fas- and FasL-deficient mice showed significant inflammation during later phases of infection accompanied by decreased expression of anti-inflammatory IL-10 and TGF-β1 cytokines and disturbances in CXCL1 and CXCL9 expression.Experiments in vitro demonstrated that ECTV-infected cultures of epithelial cells, but not macrophages, upregulate Fas and FasL and are susceptible to Fas-induced apoptosis.Our study demonstrates that Fas/FasL pathway during ECTV infection of the lungs plays an important role in controlling local inflammatory response and mounting of antiviral response.

View Article: PubMed Central - PubMed

Affiliation: Military Institute of Hygiene and Epidemiology, Kozielska 4, 01-163 Warsaw, Poland.

ABSTRACT
Fas receptor-Fas ligand (FasL) signalling is involved in apoptosis of immune cells as well as of the virus infected target cells but increasing evidence accumulates on Fas as a mediator of apoptosis-independent processes such as induction of activating and proinflammatory signals. In this study, we examined the role of Fas/FasL pathway in inflammatory and antiviral response in lungs using a mousepox model applied to C57BL6/J, B6. MRL-Faslpr/J, and B6Smn.C3-Faslgld/J mice. Ectromelia virus (ECTV) infection of Fas- and FasL-deficient mice led to increased virus titers in lungs and decreased migration of IFN-γ expressing NK cells, CD4+ T cells, CD8+ T cells, and decreased IL-15 expression. The lungs of ECTV-infected Fas- and FasL-deficient mice showed significant inflammation during later phases of infection accompanied by decreased expression of anti-inflammatory IL-10 and TGF-β1 cytokines and disturbances in CXCL1 and CXCL9 expression. Experiments in vitro demonstrated that ECTV-infected cultures of epithelial cells, but not macrophages, upregulate Fas and FasL and are susceptible to Fas-induced apoptosis. Our study demonstrates that Fas/FasL pathway during ECTV infection of the lungs plays an important role in controlling local inflammatory response and mounting of antiviral response.

No MeSH data available.


Related in: MedlinePlus

Lack of Fas or FasL during mousepox infection results in disturbances of cytokine and chemokine production. Relative mRNA levels of CXCL1, CXCL9, IL-10, IL-15, and TGF-β1 in the lungs isolated from Fas (−), FasL (−), and WT (C57BL/6) mice at 3, 7, 10, and 14 days of ECTV infection and from control, uninfected mice. The mRNA expressions were normalized by that of GAPDH, and the lungs of control, uninfected mice were estimated as 1. The bars represent the mean from 3 separate experiments ± SEM.  *Significant differences with P ≤ 0.05 and **P ≤ 0.01.
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fig4: Lack of Fas or FasL during mousepox infection results in disturbances of cytokine and chemokine production. Relative mRNA levels of CXCL1, CXCL9, IL-10, IL-15, and TGF-β1 in the lungs isolated from Fas (−), FasL (−), and WT (C57BL/6) mice at 3, 7, 10, and 14 days of ECTV infection and from control, uninfected mice. The mRNA expressions were normalized by that of GAPDH, and the lungs of control, uninfected mice were estimated as 1. The bars represent the mean from 3 separate experiments ± SEM.  *Significant differences with P ≤ 0.05 and **P ≤ 0.01.

Mentions: Taking into account the role of cytokines and chemokines in mounting an early antiviral response we tested for the levels of CXCL1, CXCL9, IL-10, and IL-15 mRNA expression in the lungs of all three mice strains during the whole ECTV infection period (Figure 4). Quantification of relative mRNA of CXCL1 in Fas- and FasL-deficient mice showed significantly increased mRNA levels of this cytokine at 3rd d.p.i. (P ≤ 0.001) and significantly decreased CXCL1 mRNA levels at 7th d.p.i. in comparison to wild-type mice (P ≤ 0.001) (Figure 4(a)). On the contrary, the levels of CXCL9 at 3rd d.p.i. ECTV infection were significantly increased in the lungs obtained from wild-type mice in comparison to Fas- and FasL-deficient mice (P ≤ 0.001) (Figure 4(b)), while at 7th d.p.i. we observed an opposite effect in the lungs of ECTV-infected Fas- and FasL-deficient mice (P ≤ 0.001) (Figure 4(b)). Many authors suggested an important role of IL-15 in mobilization of NK cells to the orthopoxvirus infected organs [27]. Following the data obtained for NK cells (Figure 3), also we observed significantly decreased expression levels of IL-15 in Fas- and FasL-deficient mice at 3rd, 7th, and 10th days of ECTV infection (Figure 4(c)). To check if the lack of Fas or FasL expression may influence production of anti-inflammatory cytokines, we tested for IL-10 and TGF-β1 mRNA levels in the lungs during ECTV infection. The Fas- and FasL-deficient mice showed significantly decreased levels of IL-10 expression early during infection (3rd and 7th d.p.i) in comparison to wild-type mice (P ≤ 0.001) (Figure 4(d)), followed by significantly decreased mRNA levels of TGF-β1 at 7th and 10th d.p.i. (P ≤ 0.05) (Figure 4(e)). In contrast, significantly increased IL-10 mRNA levels were observed in Fas- and FasL-deficient mice at 14th d.p.i (P ≤ 0.05) (Figure 4(d)). The results obtained by RT-PCR analysis were confirmed by staining of the percentage of cells positive for IL-10, IL-15, CXCL1, and CXCL9 in the cell suspensions prepared from ECTV-infected and uninfected control lungs (Table 2).


Fas/FasL pathway participates in regulation of antiviral and inflammatory response during mousepox infection of lungs.

Bień K, Sokołowska J, Bąska P, Nowak Z, Stankiewicz W, Krzyzowska M - Mediators Inflamm. (2015)

Lack of Fas or FasL during mousepox infection results in disturbances of cytokine and chemokine production. Relative mRNA levels of CXCL1, CXCL9, IL-10, IL-15, and TGF-β1 in the lungs isolated from Fas (−), FasL (−), and WT (C57BL/6) mice at 3, 7, 10, and 14 days of ECTV infection and from control, uninfected mice. The mRNA expressions were normalized by that of GAPDH, and the lungs of control, uninfected mice were estimated as 1. The bars represent the mean from 3 separate experiments ± SEM.  *Significant differences with P ≤ 0.05 and **P ≤ 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig4: Lack of Fas or FasL during mousepox infection results in disturbances of cytokine and chemokine production. Relative mRNA levels of CXCL1, CXCL9, IL-10, IL-15, and TGF-β1 in the lungs isolated from Fas (−), FasL (−), and WT (C57BL/6) mice at 3, 7, 10, and 14 days of ECTV infection and from control, uninfected mice. The mRNA expressions were normalized by that of GAPDH, and the lungs of control, uninfected mice were estimated as 1. The bars represent the mean from 3 separate experiments ± SEM.  *Significant differences with P ≤ 0.05 and **P ≤ 0.01.
Mentions: Taking into account the role of cytokines and chemokines in mounting an early antiviral response we tested for the levels of CXCL1, CXCL9, IL-10, and IL-15 mRNA expression in the lungs of all three mice strains during the whole ECTV infection period (Figure 4). Quantification of relative mRNA of CXCL1 in Fas- and FasL-deficient mice showed significantly increased mRNA levels of this cytokine at 3rd d.p.i. (P ≤ 0.001) and significantly decreased CXCL1 mRNA levels at 7th d.p.i. in comparison to wild-type mice (P ≤ 0.001) (Figure 4(a)). On the contrary, the levels of CXCL9 at 3rd d.p.i. ECTV infection were significantly increased in the lungs obtained from wild-type mice in comparison to Fas- and FasL-deficient mice (P ≤ 0.001) (Figure 4(b)), while at 7th d.p.i. we observed an opposite effect in the lungs of ECTV-infected Fas- and FasL-deficient mice (P ≤ 0.001) (Figure 4(b)). Many authors suggested an important role of IL-15 in mobilization of NK cells to the orthopoxvirus infected organs [27]. Following the data obtained for NK cells (Figure 3), also we observed significantly decreased expression levels of IL-15 in Fas- and FasL-deficient mice at 3rd, 7th, and 10th days of ECTV infection (Figure 4(c)). To check if the lack of Fas or FasL expression may influence production of anti-inflammatory cytokines, we tested for IL-10 and TGF-β1 mRNA levels in the lungs during ECTV infection. The Fas- and FasL-deficient mice showed significantly decreased levels of IL-10 expression early during infection (3rd and 7th d.p.i) in comparison to wild-type mice (P ≤ 0.001) (Figure 4(d)), followed by significantly decreased mRNA levels of TGF-β1 at 7th and 10th d.p.i. (P ≤ 0.05) (Figure 4(e)). In contrast, significantly increased IL-10 mRNA levels were observed in Fas- and FasL-deficient mice at 14th d.p.i (P ≤ 0.05) (Figure 4(d)). The results obtained by RT-PCR analysis were confirmed by staining of the percentage of cells positive for IL-10, IL-15, CXCL1, and CXCL9 in the cell suspensions prepared from ECTV-infected and uninfected control lungs (Table 2).

Bottom Line: The lungs of ECTV-infected Fas- and FasL-deficient mice showed significant inflammation during later phases of infection accompanied by decreased expression of anti-inflammatory IL-10 and TGF-β1 cytokines and disturbances in CXCL1 and CXCL9 expression.Experiments in vitro demonstrated that ECTV-infected cultures of epithelial cells, but not macrophages, upregulate Fas and FasL and are susceptible to Fas-induced apoptosis.Our study demonstrates that Fas/FasL pathway during ECTV infection of the lungs plays an important role in controlling local inflammatory response and mounting of antiviral response.

View Article: PubMed Central - PubMed

Affiliation: Military Institute of Hygiene and Epidemiology, Kozielska 4, 01-163 Warsaw, Poland.

ABSTRACT
Fas receptor-Fas ligand (FasL) signalling is involved in apoptosis of immune cells as well as of the virus infected target cells but increasing evidence accumulates on Fas as a mediator of apoptosis-independent processes such as induction of activating and proinflammatory signals. In this study, we examined the role of Fas/FasL pathway in inflammatory and antiviral response in lungs using a mousepox model applied to C57BL6/J, B6. MRL-Faslpr/J, and B6Smn.C3-Faslgld/J mice. Ectromelia virus (ECTV) infection of Fas- and FasL-deficient mice led to increased virus titers in lungs and decreased migration of IFN-γ expressing NK cells, CD4+ T cells, CD8+ T cells, and decreased IL-15 expression. The lungs of ECTV-infected Fas- and FasL-deficient mice showed significant inflammation during later phases of infection accompanied by decreased expression of anti-inflammatory IL-10 and TGF-β1 cytokines and disturbances in CXCL1 and CXCL9 expression. Experiments in vitro demonstrated that ECTV-infected cultures of epithelial cells, but not macrophages, upregulate Fas and FasL and are susceptible to Fas-induced apoptosis. Our study demonstrates that Fas/FasL pathway during ECTV infection of the lungs plays an important role in controlling local inflammatory response and mounting of antiviral response.

No MeSH data available.


Related in: MedlinePlus