Int J Oral Biol.  2017 Sep;42(3):117-121. 10.11620/IJOB.2017.42.3.117.

Inhibition of Lipopolysaccharide-stimulated Inflammatory Cytokine Production by LY303511 in Human Macrophagic THP-1 Cells

• Kim SH
• Paek YW
• Kang IC

• KMID: 2394580
• DOI: http://doi.org/10.11620/IJOB.2017.42.3.117

Abstract

We have previously shown that the specific phosphatidylinositol 3-kinase inhibitor LY294002 (LY29), and its inactive analog LY303511 (LY30), inhibit a monocyte chemoattractant protein-1 (MCP-1) expression in human umbilical vein endothelial cells; these results suggest the potential of LY30 as an anti-inflammatory drug. In this study, we determined the effects of LY30 on the production of various inflammatory cytokines in human macrophagic THP-1 cells which were stimulated with lipopolysaccharide (LPS). LY30 selectively suppressed the mRNA expression of IL-12 p40, TNF-α, and MCP-1 without affecting the expression of IL-1α, IL-6, and IL-8. Inhibition of the production of IL-12 and TNF-α by LY30 was also demonstrated using ELISA assays. In order to elucidate the mechanisms of the action of LY30, we examined the role played by the mitogen-activated protein kinases and the key transcription factors, AP-1 and NF-κB in LPS-stimulated THP-1 cells. The results revealed that LY30 inhibited LPS-induced activation of ERK, but not p38 or JNK. Furthermore, the AP-1 DNA binding activity was suppressed by LY30 based upon the dosage, whereas NF-κB DNA binding was not affected. These results suggest that LY30 selectively inhibits cytokine production in the LPS-stimulated macrophagic THP-1 cells by downregulating the activation of ERK and AP-1.

Keyword

LY303511; THP-1; cytokine; mitogen-activated protein kinase; AP-1; NF-κB

MeSH Terms

Chemokine CCL2
Cytokines
DNA
Enzyme-Linked Immunosorbent Assay
Human Umbilical Vein Endothelial Cells
Humans*
Interleukin-12
Interleukin-6
Interleukin-8
Mitogen-Activated Protein Kinases
Phosphatidylinositol 3-Kinase
RNA, Messenger
Transcription Factor AP-1
Transcription Factors
Chemokine CCL2
Cytokines
DNA
Interleukin-12
Interleukin-6
Interleukin-8
Mitogen-Activated Protein Kinases
Phosphatidylinositol 3-Kinase
RNA, Messenger
Transcription Factor AP-1
Transcription Factors