title: Matrix metalloproteinase-2 (MMP-2) generates soluble HLA-G1 by cell surface proteolytic shedding.
abstract: 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.
authors.affiliation: Section of Microbiology and Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy. rbr@unife.it
authors.forename: Roberta
authors.initials: R
authors.lastname: Rizzo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Trentini
authors.forename: Daria
authors.initials: D
authors.lastname: Bortolotti
authors.forename: Maria C
authors.initials: MC
authors.lastname: Manfrinato
authors.forename: Antonella
authors.initials: A
authors.lastname: Rotola
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Castellazzi
authors.forename: Loredana
authors.initials: L
authors.lastname: Melchiorri
authors.forename: Dario
authors.initials: D
authors.lastname: Di Luca
authors.forename: Franco
authors.initials: F
authors.lastname: Dallocchio
authors.forename: Enrico
authors.initials: E
authors.lastname: Fainardi
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bellini
mesh_terms: D000595:Amino Acid Sequence; D019138:Antibodies, Blocking / Q000494:pharmacology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D059951:HLA-G Antigens / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D059748:Proteolysis / Q000187:drug effects
chemical_list: D019138:Antibodies, Blocking; D059951:HLA-G Antigens; D003513:Cycloheximide; D004492:Edetic Acid; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9