Impairment of host defense against disseminated candidiasis in mice overexpressing GATA-3.
Candida species are the most common source of nosocomial invasive fungal infections. Previous studies have indicated that T-helper immune response is the critical host factor for susceptibility to Candida infection. The transcription factor GATA-3 is known as the master regulator for T-helper type 2 (Th2) differentiation. We therefore investigated the role of GATA-3 in the host defense against systemic Candida infection using GATA-3-overexpressing transgenic mice. The survival of GATA-3-overexpressing mice after Candida infection was significantly lower than that of wild-type mice. Candida outgrowth was significantly increased in the kidneys of GATA-3-overexpressing mice, compared with wild-type mice. The levels of various Th2 cytokines, including interleukin-4 (IL-4), IL-5, and IL-13, were significantly higher while the level of Th1 cytokine gamma interferon was significantly lower in the splenocytes of GATA-3-overexpressing mice after Candida infection. Recruitment of macrophages into the peritoneal cavity in response to Candida infection and their phagocytic activity were significantly lower in GATA-3-overexpressing mice than in wild-type mice. Exogenous administration of gamma interferon to GATA-3-overexpressing mice significantly reduced Candida outgrowth in the kidney and thus increased the survival rate. Administration of gamma interferon also increased the recruitment of macrophages into the peritoneal cavity in response to Candida infection. These results indicate that overexpression of GATA-3 modulates macrophage antifungal activity and thus enhances the susceptibility to systemic Candida infection, possibly by reducing the production of gamma interferon in response to Candida infection.
Haraguchi
Norihiro
N
Department of Respiratory Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan.
Ishii
Yukio
Y
Morishima
Yuko
Y
Yoh
Keigyou
K
Matsuno
Yosuke
Y
Kikuchi
Norihiro
N
Sakamoto
Tohru
T
Takahashi
Satoru
S
Hizawa
Nobuyuki
N
D000818:Animals; D002175:Candida / Q000276:immunology*; D002177:Candidiasis / Q000276:immunology* / Q000401:mortality; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000096:biosynthesis* / Q000276:immunology; D015870:Gene Expression; D007371:Interferon-gamma / Q000008:administration & dosage / Q000276:immunology; D007668:Kidney / Q000382:microbiology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013154:Spleen / Q000276:immunology; D016019:Survival Analysis
D016207:Cytokines; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D007371:Interferon-gamma