Objective:To study the relationship of macrophage migration inhibitory factor(MIF)/activator protein-1(AP-1)/matrix metalloproteinase-9(MMP-9)expression with inflammatory response and coronary artery lesion(CAL)in Kawasaki disease(KD).Methods:Forty-six children with KD were enrolled as the KD group, and divided into CAL group( n=17)and non-coronary artery lesion(NCAL)group( n=29). Fifteen age-and gender-matched children with lower respiratory infections and twenty children for selective operation were chosen as the control groups.Fluorescence quantitative PCR and Western blot were used to detect c-Jun/c-Fos mRNA and protein expression respectively.Serum levels of MIF/phospho-c-Jun/MMP-9 were measured by ELISA. Results:The c-Jun/c-Fos mRNA and protein expression as well as phospho-c-Jun level increased significantly in acute phase of KD as compared with those in control groups(comparison between groups: c-Jun mRNA: F=654.318, P<0.001; c-Fos mRNA: F=580.998, P<0.001; phospho-c-Jun: F=74.756, P<0.001; all P<0.05), and they were even higher in the CAL group(c-Jun mRNA: t=6.820, P<0.001; c-Fos mRNA: t=8.047, P<0.001; phospho-c-Jun: t=2.361, P=0.029; all P<0.05), then decreased in subacute phase.Serum protein levels of MIF and MMP-9 in acute phase of KD were higher than those of control groups(comparison between groups: MIF: F=104.008, P<0.001; MMP-9: F=182.798, P<0.001), and much higher in CAL group than those in NCAL group(MIF: t=2.163, P=0.043; MMP-9: t=2.104, P=0.048). There were positive correlations among serum MIF, phospho-c-Jun and MMP-9 in acute phase of KD(MIF and phospho-c-Jun: r=0.552, P<0.001; phospho-c-Jun and MMP-9: r=0.731, P<0.001; MIF and MMP-9: r=0.421, P=0.004). Conclusion:MIF/AP-1/MMP-9 signaling pathway may participate in the pathological progress of KD vasculitis and CAL.AP-1 expression and activation level in acute phase may be helpful to assess the inflammatory status and to predict CAL.

The hyphal development of Candida albicans (C. albicans) has been considered as an essential virulent factor for host cell damage. However, the missing link between hyphae and virulence of C. albicans is also been discovered. Here, we identified that the null mutants of ERG3 and ERG11, two key genes in ergosterol biosynthesis pathway, can form typical hyphae but failed to cause the oral mucosal infection in vitro and in vivo for the first time. In particular, the erg3Δ/Δ and erg11Δ/Δ strains co-cultured with epithelial cells significantly reduced the adhesion, damage, and cytokine (interleukin-1α (IL-1α)) production, whereas the invasion was not affected in vitro. Importantly, they were incapable of extensive hyphal invasion, formation of micro-abscesses, and tongue epithelium damage compared to wild type due to the decrease of the colonization and epithelial infection area in a murine oropharyngeal candidiasis model. The fluconazole (FLC), an antifungal targeted at ergosterol biosynthesis, relieved the epithelial infection of C. albicansin vitro and in vivo even under non-growth inhibitory dosage confirming the virulent contribution of ergosterol biosynthesis pathway. The erg3Δ/Δ and erg11Δ/Δ strains were cleared by macrophages similar to wild type, whereas their virulence factors including agglutinin-like sequence 1 (Als1), secreted aspartyl proteinase 6 (Sap6), and hyphal wall protein-1 (Hwp1) were significantly reduced indicated that the non-toxicity might not result from the change on immune tolerance but the defective virulence. The incapacity of erg3Δ/Δ and erg11Δ/Δ in epithelial infection highlights the contribution of ergosterol biosynthesis pathway to C. albicans pathogenesis and fluconazole can not only eliminate the fungal pathogens but also reduced their virulence even at low dosage.
Animals ; Antifungal Agents ; pharmacology ; Candida albicans ; drug effects ; genetics ; pathogenicity ; Candidiasis, Oral ; drug therapy ; genetics ; microbiology ; Fluconazole ; pharmacology ; Genes, Fungal ; genetics ; Mice ; Microscopy, Electron, Scanning ; Potassium Channels ; genetics ; Virulence