STAT6 activation by Toxoplasma gondii infection induces the expression of Th2 C-C chemokine ligands and B clade serine protease inhibitors in macrophage

Abstract

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.

Toxoplasma Rhoptry Protein 16 (ROP16) Subverts Host Function by Direct Tyrosine Phosphorylation of STAT6

“…We further demonstrate that a STAT6/ROP16 interaction can be detected from infected cells and that recombinant, purified ROP16 has intrinsic tyrosine kinase activity in vitro and can directly phosphorylate STAT6 on the crucial activation residue Tyr 641 . Together, these results indicate that ROP16 may directly activate STAT6 upon secretion into host cells; they also provide a molecular basis for observations by Ahn et al (37,38) and Saeij et al (4) that Toxoplasma induces rapid STAT6 activation in an invasiondependent manner. While this manuscript was in preparation, Yamamoto et al (39) described similar results for host STAT3.…”

Progressive Visceral Leishmaniasis Is Driven by Dominant Parasite-induced STAT6 Activation and STAT6-dependent Host Arginase 1 Expression

“…Recently, a proteophosphoglycan produced by L. mexicana within the sand fly vector was shown to induce arginase activity in inflammatory macrophages and enhance intracellular parasite replication [102]. In addition, Toxoplasma gondii was found to activate STAT6 directly [103], and induce arginase through TLR-dependent, but STAT6-independent pathway [104]. Lastly, it was demonstrated that the Ym1, another marker of alternative activation, was induced in macrophages exposed to a helminth antigen [105].…”

Genome-wide Profiling of Interleukin-4 and STAT6 Transcription Factor Regulation of Human Th2 Cell Programming

“…To our knowledge, only 6% of the target genes in our RNAi data are reported to be regulated by STAT6, by using genome-wide screens performed either on T or B cells of Stat6 À/À mice or STAT6-RNAi experiments, or bound by STAT6 in electrophoretic mobility shift assay (EMSA) (Table S1) (Ahn et al, 2009;Arpa et al, 2009;Bü ttner et al, 2004;Chen et al, 2003;Filen et al, 2009;Gabay et al, 1999;Hebenstreit et al, 2003;Kim et al, 2006;Kurata et al, 1999;Lund et al, 2007;McGaha et al, 2003;Ohmori et al, 1996;Schaefer et al, 2001;Schrö der et al, 2002;Yang et al, 2005;Zhang et al, 2000;Zhu et al, 2002). In addition, few of the genes, such as MAOA, are suggested to be regulated by STAT6 by using indirect methods such as in silico predictions (Chaitidis et al, 2004).…”