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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 liver.Activity levels of (a) cathepsin H; (b) cathepsin C; (c) cathepsin B and (d) cathepsin L in the liver of all groups of animals. *P<0.05 (compared with control mice group, Group-I); #P<0.05, values significantly different from infected groups (Group II and III) of mice.
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Figure 5: Activity levels of cathepsins in liver.Activity levels of (a) cathepsin H; (b) cathepsin C; (c) cathepsin B and (d) cathepsin L in the liver of all groups of animals. *P<0.05 (compared with control mice group, Group-I); #P<0.05, values significantly different from infected groups (Group II and III) of mice.

Mentions: Similar to kidney, increased and decreased in the CPC and CPL activities (fig. 5b and d, respectively) were also observed in the liver tissues under both conditions, that is in the infected (Group II and III) and antifungal treated (Group IV and V) groups. While opposing to kidney, major alterations in the levels of other cathepsins (CPB and CPH) were also observed in the liver in all groups of compared with control. As shown in fig. 5c, CPB activity was also detected high (~1.5- to 3.0-fold) in the infected groups (Gp II and III) compared with control, however, this activity gets reversed after antifungal treatments and come to the level of control group. Contrary to all cathepsins studied under present investigations, CPH activity pattern was found altogether different in both conditions (fig. 5a). The activity of this enzyme was noticed significantly low in the liver tissue of the infected groups of mice (Group II and III) while its level gets up-regulated after the treatment (Group IV and V). In other words, CPH works opposite to CPB, CPC and CPL in both infected and treated groups of mice (fig. 5a). One possible reason could be the inhibitory effect of some metabolites secreted by fungus, which may be responsible for decreasing the CPH activity after infection but this regulatory effect of these metabolites gets reversed after antifungal treatment.


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 liver.Activity levels of (a) cathepsin H; (b) cathepsin C; (c) cathepsin B and (d) cathepsin L in the liver of all groups of animals. *P<0.05 (compared with control mice group, Group-I); #P<0.05, values significantly different from 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 5: Activity levels of cathepsins in liver.Activity levels of (a) cathepsin H; (b) cathepsin C; (c) cathepsin B and (d) cathepsin L in the liver of all groups of animals. *P<0.05 (compared with control mice group, Group-I); #P<0.05, values significantly different from infected groups (Group II and III) of mice.
Mentions: Similar to kidney, increased and decreased in the CPC and CPL activities (fig. 5b and d, respectively) were also observed in the liver tissues under both conditions, that is in the infected (Group II and III) and antifungal treated (Group IV and V) groups. While opposing to kidney, major alterations in the levels of other cathepsins (CPB and CPH) were also observed in the liver in all groups of compared with control. As shown in fig. 5c, CPB activity was also detected high (~1.5- to 3.0-fold) in the infected groups (Gp II and III) compared with control, however, this activity gets reversed after antifungal treatments and come to the level of control group. Contrary to all cathepsins studied under present investigations, CPH activity pattern was found altogether different in both conditions (fig. 5a). The activity of this enzyme was noticed significantly low in the liver tissue of the infected groups of mice (Group II and III) while its level gets up-regulated after the treatment (Group IV and V). In other words, CPH works opposite to CPB, CPC and CPL in both infected and treated groups of mice (fig. 5a). One possible reason could be the inhibitory effect of some metabolites secreted by fungus, which may be responsible for decreasing the CPH activity after infection but this regulatory effect of these metabolites gets reversed after antifungal treatment.

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