MFHAS1 Is Associated with Sepsis and Stimulates TLR2/NF-κB Signaling Pathway Following Negative Regulation

PLoS One. 2015 Nov 24;10(11):e0143662. doi: 10.1371/journal.pone.0143662. eCollection 2015.

Abstract

Malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) has a potential immunoregulatory role dependent on Toll-like receptors (TLRs). TLR2, associated with deleterious systemic inflammation, cardiac dysfunction, and acute kidney injury, acts synergistically in sepsis. The role of MFHAS1 in targeting TLR2 involved in sepsis has not been examined thus far. This study aimed to examine the relationship of MFHAS1 and sepsis, and the effect of MFHAS1 on the TLR2 signaling pathway. Blood samples were collected from eight sepsis patients after surgery and eight patients undergoing selective surgery to determine blood MFHAS1 levels. HEK 293 cells, RAW 264.7 macrophages and THP-1 monocytes were used to confirm the effect of MFHAS1 on TLR2 signaling pathway. Our study showed that blood MFHAS1 was significantly elevated in septic patients, and MFHAS1 was more increased in mononuclear cells from septic patients. Pam3CSK4 (TLR2 ligand) was found to induce MFHAS1 production in RAW 264.7 murine macrophages and THP-1 human monocytes in a time-dependent manner. MFHAS1 has dual effects on TLR2 signaling pathway and inflammation, i.e., inhibitory effect at 6 hours, and then stimulatory effect after 24 hours through the activation of TLR2/NF-κB signaling pathway, and MFHAS1 induced the phosphorylation of JNK and p38 after TLR2 stimulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Blotting, Western
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • HEK293 Cells
  • Humans
  • Interleukin-6 / metabolism*
  • Lipopeptides / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Middle Aged
  • Monocytes / drug effects
  • Monocytes / metabolism
  • NF-kappa B / metabolism*
  • Oncogene Proteins / metabolism*
  • Rats
  • Sepsis / metabolism*
  • Signal Transduction / drug effects
  • Toll-Like Receptor 2 / agonists
  • Toll-Like Receptor 2 / metabolism*

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Interleukin-6
  • Lipopeptides
  • MFHAS1 protein, human
  • NF-kappa B
  • Oncogene Proteins
  • Pam(3)CSK(4) peptide
  • Toll-Like Receptor 2

Grant support

This study was funded by grants from Ministry of Education of the People’s Republic of China No. 20110071110044; URL: http://www.moe.gov.cn/ to CHM and the Shanghai Municipal Commission of Health and Family Planning No. 20144Y0173; URL: http://www.wsjsw.gov.cn/wsj/ to JZ.