title: Intracellular Networks of the PI3K/AKT and MAPK Pathways for Regulating Toxoplasma gondii-Induced IL-23 and IL-12 Production in Human THP-1 Cells.
abstract: Interleukin (IL)-23 and IL-12 are closely related in structure, and these cytokines regulate both innate and adaptive immunity. However, the precise signaling networks that regulate the production of each in Toxoplasma gondii-infected THP-1 monocytic cells, particularly the PI3K/AKT and MAPK signaling pathways, remain unknown. In the present study, T. gondii infection upregulated the expression of IL-23 and IL-12 in THP-1 cells, and both cytokines increased with parasite dose. IL-23 secretion was strongly inhibited by TLR2 monoclonal antibody (mAb) treatment in a dose-dependent manner and by TLR2 siRNA transfection, whereas IL-12 secretion was strongly inhibited by TLR4 mAb treatment dose-dependently and by TLR4 siRNA transfection. IL-23 production was dose-dependently inhibited by the PI3K inhibitors LY294002 and wortmannin, whereas IL-12 production increased dose-dependently. THP-1 cells exposed to live T. gondii tachyzoites underwent rapid p38 MAPK, ERK1/2 and JNK activation. IL-23 production was significantly upregulated by the p38 MAPK inhibitor SB203580 dose-dependently, whereas pretreatment with 10 μM SB203580 significantly downregulated IL-12 production. ERK1/2 inhibition by PD98059 was significantly downregulated IL-23 production but upregulated IL-12 production. JNK inhibition by SP600125 upregulated IL-23 production, but IL-12 production was significantly downregulated dose-dependently. T. gondii infection resulted in AKT activation, and AKT phosphorylation was inhibited dose-dependently after pretreatment with PI3K inhibitors. In T. gondii-infected THP-1 cells, ERK1/2 activation was regulated by PI3K; however, the phosphorylation of p38 MAPK and JNK was negatively modulated by the PI3K signaling pathway. Collectively, these results indicate that IL-23 production in T. gondii-infected THP-1 cells was regulated mainly by TLR2 and then by PI3K and ERK1/2; however, IL-12 production was mainly regulated by TLR4 and then by p38 MAPK and JNK. Our findings provide new insight concerning the intracellular networks of the PI3K/AKT and MAPK signaling cascades for regulating T. gondii-induced IL-23 and IL-12 secretion in human monocytic cells.
authors.affiliation: Department of Gastroenterology, The Affiliated Hospital of Guangdong Medical College, Zhanjiang 524-001, Guangdong, China.
authors.forename: Juan-Hua
authors.initials: JH
authors.lastname: Quan
authors.affiliation: Stem Cell Research and Cellular Therapy Center, The Affiliated Hospital of Guangdong Medical College, Zhanjiang, 524-001, China.
authors.forename: Jia-Qi
authors.initials: JQ
authors.lastname: Chu
authors.affiliation: Department of Medical Education, Chungnam National University School of Medicine, Daejeon, 301-131, Korea.
authors.forename: Jaeyul
authors.initials: J
authors.lastname: Kwon
authors.affiliation: Department of Infection Biology, Chungnam National University School of Medicine, Daejeon, 301-131, Korea.
authors.forename: In-Wook
authors.initials: IW
authors.lastname: Choi
authors.affiliation: Department of Infection Biology, Chungnam National University School of Medicine, Daejeon, 301-131, Korea.
authors.forename: Hassan Ahmed Hassan Ahmed
authors.initials: HA
authors.lastname: Ismail
authors.affiliation: Department of Infection Biology, Chungnam National University School of Medicine, Daejeon, 301-131, Korea.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Infection Biology, Chungnam National University School of Medicine, Daejeon, 301-131, Korea.
authors.forename: Guang-Ho
authors.initials: GH
authors.lastname: Cha
authors.affiliation: Department of Gastroenterology, The Affiliated Hospital of Guangdong Medical College, Zhanjiang 524-001, Guangdong, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Infection Biology, Chungnam National University School of Medicine, Daejeon, 301-131, Korea.
authors.forename: Jae-Min
authors.initials: JM
authors.lastname: Yuk
authors.affiliation: Department of Microbiology and Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, 301-131, Korea.
authors.forename: Eun-Kyeong
authors.initials: EK
authors.lastname: Jo
authors.affiliation: Department of Infection Biology, Chungnam National University School of Medicine, Daejeon, 301-131, Korea.
authors.forename: Young-Ha
authors.initials: YH
authors.lastname: Lee
mesh_terms: D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis*; D053759:Interleukin-23 / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014122:Toxoplasma; D014123:Toxoplasmosis / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D018664:Interleukin-12; D053759:Interleukin-23; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases