α/2-Macroglobulin modulates the immunoregulatory function of the lipocalin placental protein 14

Abstract

Human placental protein 14 (PP14; also known as glycodelin and progesterone-associated endometrial protein) is an immunosuppressive protein of the lipocalin structural superfamily. Mechanisms regulating serum PP14's immunosuppressive activity remain to be elucidated. In the present study, an interaction between PP14 and a major serum protein carrier, α2-macroglobulin (α2M), was documented for the first time. Using native gel electrophoresis, we showed that PP14, as well as its alternative splice variant PP14.2, binds to both α2M and methylamineactivated (MA)-α2M. Cross-competition studies demonstrated that the variants compete for binding to α2M. PP14. bound to α2M and MA-α2M with K(d) values of 167 ± 70 and 221 ± 56 nM (means±S.D.) respectively, as determined by surface plasmon resonance. Significantly, the addition of α2M or MA-α2M to a T-cell proliferation assay strongly potentiated the inhibitory capacity of PP14. On the basis of these findings, α2M emerges as the first serum protein that can physically associate with, and thereby regulate, PP14. Moreover, this represents the first documented interaction between the protein carrier α2M and a lipocalin protein.