STAT6 activation by Toxoplasma gondii infection induces the expression of Th2 C-C chemokine ligands and B clade serine protease inhibitors in macrophage.
Toxoplasma gondii provoked rapid and sustained nuclear translocation of signal transducer and activator of transcription (STAT) 6, a central mediator of interleukin (IL)-4, in macrophage-differentiated human acute monocytic leukemia cells without exogenous IL-4 in western blot and immunofluorescence assay. Phosphorylation of STAT6 occurred immediately after the entry of T. gondii and only by live tachyzoites, not by killed or soluble extract. It was impeded by Janus kinase (JAK) 3 inhibitor and small interfering RNA (siRNA) of STAT6. It induced expression of IL-4 responsive genes such as IL-4R, CD40, and CD23. It also mediated expression of two large clusters of C-C chemokine ligands (CCLs) and serine protease inhibitors (SERPINs) in microarray of T. gondii-infected macrophages. CCL1, 2, 8, 13, and 22 and SPINT2, SERPINB3, B4, and B13 were increased by the infection and inhibited by the treatment of JAK3 inhibitor and siRNA-mediated STAT6 silencing, which suggested the expression was governed by STAT6 activation. Secreting those CCLs, T. gondii-infected macrophages may attract more monocytes and Th2 cells of CCR3 and CCR4 to enrich the Th2 environment nearby the infected macrophages, and induced SERPINs may participate in protection from intracellular damages produced by activated lysosomal enzymes and in the inhibition of caspase activity to block the apoptosis. This suggests that T. gondii exploits cytokine cross-regulation through STAT6 activation to obviate various toxoplasmacidal reactions by interferon-gamma.
Ahn
Hye-Jin
HJ
Department of Parasitology and the Catholic Institute of Parasitic Diseases, College of Medicine, Catholic University of Korea, Seoul 137-701, South Korea.
Kim
Ji Yeon
JY
Ryu
Kyung-Ju
KJ
Nam
Ho-Woo
HW
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line; D019742:Chemokines, CC / Q000096:biosynthesis*; D006801:Humans; D008264:Macrophages / Q000276:immunology*; D009000:Monocytes / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D015843:Serpins / Q000096:biosynthesis*; D018418:Th2 Cells / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology*
D019742:Chemokines, CC; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015843:Serpins