MAPK-activated protein kinase 2 differentially regulates plasmodium falciparum glycosylphosphatidylinositol-induced production of tumor necrosis factor-{alpha} and interleukin-12 in macrophages.
Proinflammatory responses induced by Plasmodium falciparum glycosylphosphatidylinositols (GPIs) are thought to be involved in malaria pathogenesis. In this study, we investigated the role of MAPK-activated protein kinase 2 (MK2) in the regulation of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-12, two of the major inflammatory cytokines produced by macrophages stimulated with GPIs. We show that MK2 differentially regulates the GPI-induced production of TNF-alpha and IL-12. Although TNF-alpha production was markedly decreased, IL-12 expression was increased by 2-3-fold in GPI-stimulated MK2(-/-) macrophages compared with wild type (WT) cells. MK2(-/-) macrophages produced markedly decreased levels of TNF-alpha than WT macrophages mainly because of lower mRNA stability and translation. In the case of IL-12, mRNA was substantially higher in MK2(-/-) macrophages than WT. This enhanced production is due to increased NF-kappaB binding to the gene promoter, a markedly lower level expression of the transcriptional repressor factor c-Maf, and a decreased binding of GAP-12 to the gene promoter in MK2(-/-) macrophages. Thus, our data demonstrate for the first time the role of MK2 in the transcriptional regulation of IL-12. Using the protein kinase inhibitors SB203580 and U0126, we also show that the ERK and p38 pathways regulate TNF-alpha and IL-12 production, and that both inhibitors can reduce phosphorylation of MK2 in response to GPIs and other toll-like receptor ligands. These results may have important implications for developing therapeutics for malaria and other infectious diseases.
Zhu
Jianzhong
J
Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Wu
Xianzhu
X
Goel
Suchi
S
Gowda
Nagaraj M
NM
Kumar
Sanjeev
S
Krishnegowda
Gowdahalli
G
Mishra
Gourav
G
Weinberg
Rebecca
R
Li
Guangfu
G
Gaestel
Matthias
M
Muta
Tatsushi
T
Gowda
D Channe
DC
D000818:Animals; D001854:Bone Marrow Cells / Q000469:parasitology; D017931:DNA Primers; D004912:Erythrocytes / Q000469:parasitology; D005786:Gene Expression Regulation; D017261:Glycosylphosphatidylinositols / Q000494:pharmacology*; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis*; D048370:MAP Kinase Kinase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000469:parasitology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010963:Plasmodium falciparum / Q000201:enzymology*; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D017931:DNA Primers; D017261:Glycosylphosphatidylinositols; D016328:NF-kappa B; D015800:Protozoan Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D012313:RNA; D048370:MAP Kinase Kinase 2