Chemokine CCL28 induces apoptosis of decidual stromal cells via binding CCR3/CCR10 in human spontaneous abortion

Mol Hum Reprod. 2013 Oct;19(10):676-86. doi: 10.1093/molehr/gat038. Epub 2013 Jun 4.

Abstract

Spontaneous abortion is the most common complication of pregnancy. Immune activation and the subsequent inflammation-induced tissue injury are often observed at the maternal-fetal interface as the final pathological assault in recurrent spontaneous abortion. However, the precise mechanisms responsible for spontaneous abortion involving inflammation are not fully understood. Chemokine CCL28 and its receptors CCR3 and CCR10 are important regulators in inflammatory process. Here, we examined the expression of CCL28 and its receptors in decidual stromal cells (DSCs) by immunochemistry and flow cytometry (FCM), and compared their expression level in DSCs from normal pregnancy versus spontaneous abortion, and their relationship to inflammatory cytokines production by DSCs. We further analyzed regulation of the pro-inflammatory cytokines on CCL28 expression in DSCs by real-time polymerase chain reaction, In-cell Western and FCM. The effects of CCL28-CCR3/CCR10 interaction on DSC apoptosis was investigated by Annexin V staining and FCM analysis or DAPI staining and nuclear morphology. Higher levels of the inflammatory cytokines interleukin (IL)-1β, IL-17A and tumor necrosis factor-α, and increased CCR3/CCR10 expression were observed in DSCs from spontaneous abortion compared with normal pregnancy. Treatment with inflammatory cytokines differently affected CCL28 and CCR3/CCR10 expression in DSCs. Human recombinant CCL28 promoted DSC apoptosis, which was eliminated by pretreatment with neutralizing antibodies against CCR3/CCR10 and CCL28. However, CCL28 did not affect DSC growth. These results suggest that the inflammation-promoted up-regulation of CCL28 and its receptors interaction in DSCs is involved in human spontaneous abortion via inducing DSC apoptosis.

Keywords: CCL28; apoptosis; decidual stromal cells; inflammatory cytokine; spontaneous abortion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abortion, Spontaneous / genetics
  • Abortion, Spontaneous / metabolism*
  • Adult
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cells, Cultured
  • Chemokines, CC / genetics
  • Chemokines, CC / metabolism*
  • Decidua / cytology*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • In Vitro Techniques
  • Interleukin-17 / pharmacology
  • Interleukin-1beta / pharmacology
  • Pregnancy
  • Receptors, CCR10 / genetics
  • Receptors, CCR10 / metabolism*
  • Receptors, CCR3 / genetics
  • Receptors, CCR3 / metabolism*
  • Stromal Cells / cytology*
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Young Adult

Substances

  • CCL28 protein, human
  • CCR10 protein, human
  • CCR3 protein, human
  • Chemokines, CC
  • Interleukin-17
  • Interleukin-1beta
  • Receptors, CCR10
  • Receptors, CCR3
  • Tumor Necrosis Factor-alpha