Molecular and Cellular Biochemistry

, Volume 381, Issue 1–2, pp 243–255 | Cite as

Matrix metalloproteinase-2 (MMP-2) generates soluble HLA-G1 by cell surface proteolytic shedding

  • Roberta RizzoEmail author
  • Alessandro Trentini
  • Daria Bortolotti
  • Maria C. Manfrinato
  • Antonella Rotola
  • Massimiliano Castellazzi
  • Loredana Melchiorri
  • Dario Di Luca
  • Franco Dallocchio
  • Enrico Fainardi
  • Tiziana Bellini


Human leukocyte antigen-G (HLA-G) molecules are non-classical HLA class I antigens with an important role in pregnancy immune regulation and inflammation control. Soluble HLA-G proteins can be generated through two mechanisms: alternative splicing and proteolytic release, which is known to be metalloprotease mediated. Among this class of enzymes, matrix metalloproteinases (MMPs) might be involved in the HLA-G1 membrane cleavage. Of particular interest are MMP-2 and MMP-9, which regulate the inflammatory process by cytokine and chemokine modulation. We evaluated the effect of MMP-9 and MMP-2 on HLA-G1 membrane shedding. In particular, we analyzed the in vitro effect of these two gelatinases on the secretion of HLA-G1 via proteolytic cleavage in 221-G1-transfected cell line, in JEG3 cell line, and in peripheral blood mononuclear cells. The results obtained by both cell lines showed the role of MMP-2 in HLA-G1 shedding. On the contrary, MMP-9 was not involved in this process. In addition, we identified three possible highly specific cleavage sites for MMP-2, whereas none were detected for MMP-9. This study suggests an effective link between MMP-2 and HLA-G1 shedding, increasing our knowledge on the regulatory machinery beyond HLA-G regulation in physiological and pathological conditions.


HLA-G Matrix metalloproteinase Protein shedding Inflammation 



Human leukocyte antigen-G




Matrix metalloproteinase


A disintegrin and metalloproteinase



We thank Iva Pivanti for her skillful technical assistance. We also thank Linda Marie Sartor for revision of the English language. This work was supported by the Research Program Regione Emilia Romagna—University 2007–2009 (Innovative Research)—code PRUa1a-2007-008.

Supplementary material

11010_2013_1708_MOESM1_ESM.tif (4.8 mb)
Supplementary Fig. 1. Zymogram of MMP-9 and MMP-2 after 2-hr incubation. Both MMP-9 and MMP-2 were activated (MMP-9: 82 kDa and 66 kDa band; MMP-2 66 kDa band)
11010_2013_1708_MOESM2_ESM.tif (573 kb)
Supplementary Fig. 2. HLA-G5 levels in 221-G1 culture supernatants in a) FBS-free culture condition, b) after MMP-2 and EDTA treatment, and c) MMP-2 and cycloheximide (CYCLO). The cell culture supernatants were analyzed with 5A6G7 moAb (Exbio) specific for HLA-G5 isoform


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Roberta Rizzo
    • 1
    Email author
  • Alessandro Trentini
    • 2
  • Daria Bortolotti
    • 1
  • Maria C. Manfrinato
    • 2
  • Antonella Rotola
    • 1
  • Massimiliano Castellazzi
    • 2
  • Loredana Melchiorri
    • 1
  • Dario Di Luca
    • 1
  • Franco Dallocchio
    • 2
  • Enrico Fainardi
    • 3
  • Tiziana Bellini
    • 2
  1. 1.Section of Microbiology and Medical Genetics, Department of Medical SciencesUniversity of FerraraFerraraItaly
  2. 2.Department of Biomedical and Surgical SciencesUniversity of FerraraFerraraItaly
  3. 3.Neuroradiology Unit, Department of Neurosciences and RehabilitationAzienda Ospedaliera-Universitaria di FerraraFerraraItaly

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