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Antifungal Treatments Delineate a Correlation between Cathepsins and Cytokines in Murine Model of Invasive Aspergillosis.

Mittal A, Gahlaut A, Sharma GL, Dabur R - Indian J Pharm Sci (2013)

Bottom Line: In the present murine model of invasive pulmonary aspergillosis, on seventh day of Aspergillus fumigatus infection, both kidney and liver showed significant (P<0.05) fungal burdens, which was also confirmed by histological analyses.The data illustrate that the reduction in fungal load in both organs probably results in a decreased local inflammatory response, as measured by decreased levels of interleukin-4 and interleukin-10 and increased level of interferon gamma in the antifungal compounds treated mice.Interestingly, this altered level of cytokines relates well with the activity level of cathepsins, that is decreased in interleukines (interleukinL-4/interleukin-10) and cathepsins (cathepsin B, cathepsin C and cathepsin L); and increase in interferon gamma and cathepsin H levels in the mice treated with antifungal compounds were observed.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University College, Kurukshetra University, Kurukshetra-136 119, India.

ABSTRACT
In the pathogenesis of invasive pulmonary aspergillosis both fungal and host factors play roles. Though cytokines and phagocyte, as host factors, have been shown to participate in defence against Aspergillus species yet the role of cysteine proteases, that is cathepsins, a lysosomal enzymes of phagocytes, remains unknown in fungal infection. Studies are available which shows that cytokines regulate the cysteine proteases processed immune molecules for their further action but their relationship with each other under fungal infection is not clear. Therefore, in this study, we demonstrate the substantial role of cathepsins and cytokines in aspergillosis. In the present murine model of invasive pulmonary aspergillosis, on seventh day of Aspergillus fumigatus infection, both kidney and liver showed significant (P<0.05) fungal burdens, which was also confirmed by histological analyses. The activity profiles of four cathepsins in the kidney and liver tissue were analysed and correlated with blood cytokines level in the presence and absence of antifungal compounds (amphotericin B, a standard drug and 2-(3,4-dimethyl-2,5-dihydro-1H-pyrrole-2-yl)-1-methylethyl pentanoate, isolated in our laboratory from natural source) treatment. The data illustrate that the reduction in fungal load in both organs probably results in a decreased local inflammatory response, as measured by decreased levels of interleukin-4 and interleukin-10 and increased level of interferon gamma in the antifungal compounds treated mice. Interestingly, this altered level of cytokines relates well with the activity level of cathepsins, that is decreased in interleukines (interleukinL-4/interleukin-10) and cathepsins (cathepsin B, cathepsin C and cathepsin L); and increase in interferon gamma and cathepsin H levels in the mice treated with antifungal compounds were observed. These observations support not only the negative (cathepsin B, cathepsin C and cathepsin L) and positive (cathepsin H) role of cathepsins in aspergillosis but also prove the role of cytokines in remodelling of immune response. Overall, the study reveals a correlation between cathepsins and cytokines and their regulatory role in fungal mediated infection.

No MeSH data available.


Related in: MedlinePlus

Activity levels of cathepsins in kidney.Activity levels of (a) cathepsin H; (b) cathepsin C; (c) cathepsin B and (d) cathepsin L in the kidney of all groups of animals. *P<0.05 (compared with control mice group, Group-I); #P<0.05, values significantly different form infected groups (Group II and III) of mice.
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Figure 4: Activity levels of cathepsins in kidney.Activity levels of (a) cathepsin H; (b) cathepsin C; (c) cathepsin B and (d) cathepsin L in the kidney of all groups of animals. *P<0.05 (compared with control mice group, Group-I); #P<0.05, values significantly different form infected groups (Group II and III) of mice.

Mentions: To explore any regulatory role of host-factor (specifically, cathepsins) in fungal mediated disease progression, we examined the activity profile of these enzymes (CPB, CPL, CPC, CPH) in all five groups, that is under infected and treated conditions. As seen in fig. 4b, A. fumigatus infection (Group II and III) resulted in a significant increase in CPC activity level, with a further ~3.0 fold increase above control. However, the activity of this enzyme was found low in groups (Group IV and V) treated with antifungal compounds. Likewise the activity level of another cathepsin, that is CPL was also observed high (~1.5 fold) in infected groups of mice if compared with control and this activity get decreased after antifungal treatment (fig. 4d). Downregulation in the activity of CPC (~100% inhibition by DHP and 60% inhibition by AmpB) and CPL (~20-30% inhibition by both compounds) after treatment indicates the physiological importance of these enzymes in progression of aspergillosis in kidney organ of the mice. Evidences are available which explained that cathepsin L activates cathepsin C, which further activates other cathepsins and enzymes[28]. Our data also supports this evidence, an elevation in CPL activity (fig. 4d, Group II and III) possibly activates CPC and once CPC gets activated, it may undergo autocatalysis, which further resulted more increase in the CPC activity (fig. 4b, Group II and III). Furthermore, literature reports that cathepsin C is one of the major processing enzymes known so far. It activates a number of serine granule enzymes, granzymes A and B, cathepsin G, neutrophil elastrase and chymase[29]. Likewise in antifungal treated groups a sharp decrease in CPC activity compared with CPL, further elaborate the possibility that after diminishing the effect of antifungal compounds CPL would reactivate the CPC activity. Additionally, elevated level of cathepsins is harmful to the cell/tissues as it may lead to cell death and help fungus in its progression. In contrast to these cathepsins, no significant change in the activity profile of CPB and CPH was observed in all groups of mice under investigations (fig. 4a and c).


Antifungal Treatments Delineate a Correlation between Cathepsins and Cytokines in Murine Model of Invasive Aspergillosis.

Mittal A, Gahlaut A, Sharma GL, Dabur R - Indian J Pharm Sci (2013)

Activity levels of cathepsins in kidney.Activity levels of (a) cathepsin H; (b) cathepsin C; (c) cathepsin B and (d) cathepsin L in the kidney of all groups of animals. *P<0.05 (compared with control mice group, Group-I); #P<0.05, values significantly different form infected groups (Group II and III) of mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928733&req=5

Figure 4: Activity levels of cathepsins in kidney.Activity levels of (a) cathepsin H; (b) cathepsin C; (c) cathepsin B and (d) cathepsin L in the kidney of all groups of animals. *P<0.05 (compared with control mice group, Group-I); #P<0.05, values significantly different form infected groups (Group II and III) of mice.
Mentions: To explore any regulatory role of host-factor (specifically, cathepsins) in fungal mediated disease progression, we examined the activity profile of these enzymes (CPB, CPL, CPC, CPH) in all five groups, that is under infected and treated conditions. As seen in fig. 4b, A. fumigatus infection (Group II and III) resulted in a significant increase in CPC activity level, with a further ~3.0 fold increase above control. However, the activity of this enzyme was found low in groups (Group IV and V) treated with antifungal compounds. Likewise the activity level of another cathepsin, that is CPL was also observed high (~1.5 fold) in infected groups of mice if compared with control and this activity get decreased after antifungal treatment (fig. 4d). Downregulation in the activity of CPC (~100% inhibition by DHP and 60% inhibition by AmpB) and CPL (~20-30% inhibition by both compounds) after treatment indicates the physiological importance of these enzymes in progression of aspergillosis in kidney organ of the mice. Evidences are available which explained that cathepsin L activates cathepsin C, which further activates other cathepsins and enzymes[28]. Our data also supports this evidence, an elevation in CPL activity (fig. 4d, Group II and III) possibly activates CPC and once CPC gets activated, it may undergo autocatalysis, which further resulted more increase in the CPC activity (fig. 4b, Group II and III). Furthermore, literature reports that cathepsin C is one of the major processing enzymes known so far. It activates a number of serine granule enzymes, granzymes A and B, cathepsin G, neutrophil elastrase and chymase[29]. Likewise in antifungal treated groups a sharp decrease in CPC activity compared with CPL, further elaborate the possibility that after diminishing the effect of antifungal compounds CPL would reactivate the CPC activity. Additionally, elevated level of cathepsins is harmful to the cell/tissues as it may lead to cell death and help fungus in its progression. In contrast to these cathepsins, no significant change in the activity profile of CPB and CPH was observed in all groups of mice under investigations (fig. 4a and c).

Bottom Line: In the present murine model of invasive pulmonary aspergillosis, on seventh day of Aspergillus fumigatus infection, both kidney and liver showed significant (P<0.05) fungal burdens, which was also confirmed by histological analyses.The data illustrate that the reduction in fungal load in both organs probably results in a decreased local inflammatory response, as measured by decreased levels of interleukin-4 and interleukin-10 and increased level of interferon gamma in the antifungal compounds treated mice.Interestingly, this altered level of cytokines relates well with the activity level of cathepsins, that is decreased in interleukines (interleukinL-4/interleukin-10) and cathepsins (cathepsin B, cathepsin C and cathepsin L); and increase in interferon gamma and cathepsin H levels in the mice treated with antifungal compounds were observed.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University College, Kurukshetra University, Kurukshetra-136 119, India.

ABSTRACT
In the pathogenesis of invasive pulmonary aspergillosis both fungal and host factors play roles. Though cytokines and phagocyte, as host factors, have been shown to participate in defence against Aspergillus species yet the role of cysteine proteases, that is cathepsins, a lysosomal enzymes of phagocytes, remains unknown in fungal infection. Studies are available which shows that cytokines regulate the cysteine proteases processed immune molecules for their further action but their relationship with each other under fungal infection is not clear. Therefore, in this study, we demonstrate the substantial role of cathepsins and cytokines in aspergillosis. In the present murine model of invasive pulmonary aspergillosis, on seventh day of Aspergillus fumigatus infection, both kidney and liver showed significant (P<0.05) fungal burdens, which was also confirmed by histological analyses. The activity profiles of four cathepsins in the kidney and liver tissue were analysed and correlated with blood cytokines level in the presence and absence of antifungal compounds (amphotericin B, a standard drug and 2-(3,4-dimethyl-2,5-dihydro-1H-pyrrole-2-yl)-1-methylethyl pentanoate, isolated in our laboratory from natural source) treatment. The data illustrate that the reduction in fungal load in both organs probably results in a decreased local inflammatory response, as measured by decreased levels of interleukin-4 and interleukin-10 and increased level of interferon gamma in the antifungal compounds treated mice. Interestingly, this altered level of cytokines relates well with the activity level of cathepsins, that is decreased in interleukines (interleukinL-4/interleukin-10) and cathepsins (cathepsin B, cathepsin C and cathepsin L); and increase in interferon gamma and cathepsin H levels in the mice treated with antifungal compounds were observed. These observations support not only the negative (cathepsin B, cathepsin C and cathepsin L) and positive (cathepsin H) role of cathepsins in aspergillosis but also prove the role of cytokines in remodelling of immune response. Overall, the study reveals a correlation between cathepsins and cytokines and their regulatory role in fungal mediated infection.

No MeSH data available.


Related in: MedlinePlus