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Hormonal Regulation and Tissue-Specific Localization of ₂-Macroglobulin in Rat Ovarian Follicles and Corpora Lutea^*

Department of Cell Biology, Baylor College of Medicine Houston, Texas 77030
Department of Immunology, Research Institute of Scripps Clinic La Jolla, California 92037
Molecular Virology and Immunology Program, Department of Pathology, McMaster University Hamilton, Ontario, Canada L8N 3Z5

Address requests for reprints to: JoAnne S. Richards, Department of Cell Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030.

Abstract

₂-Macroglobulin (₂M) is a broad spectrum protease inhibitor associated with inflammatory responses and proposed to be important in tissue remodeling. ₂M also functions as a carrier of specific growth factors and cytokines, including platelet-derived growth factor, transforming growth factor-β, basic fibroblast growth factor, interleukin-1, and interleukin- 6. To determine whether ₂M is associated with remodeling phenomena in the rat ovary, the expression of ₂M mRNA and protein has been analyzed in specific ovarian cell types during ovulation, luteinization, and luteolysis. Before ovulation, ₂M mRNA is not detectable in granulosa cells. Twelve hours after injection of an ovulatory dose of hCG a 5.2-kilobase ₂M mRNA is detectable in luteinizing follicles, which is increased further by 48 h and maintained in corpora lutea (CL) for up to 96 h. Administration of PRL from 24–96 h results in both inhibition of luteolysis and marked increases in ₂M mRNA in CL, but not in residual tissues, of these same ovaries, isolated 48, 72, and 96 h after an ovulatory dose of hCG. ₂M mRNA is also induced by PRL in cultures of luteinized granulosa cells.

These changes in ₂M mRNA in follicles or developing CL do not appear to reflect the amount of ₂M protein present; ₂M protein (188K monomer) is present (immunoblot and immunofluorescence data) in small antral and preovulatory follicles even though mRNA is not detectable; after an ovulatory dose of hCG the protein level transiently increases by 12 h (5-fold) and declines thereafter through 96 h; the decrease in ₂M protein observed at 48–96 h is delayed but not abolished by treatment with PRL, even though the mRNA levels continue to rise during this same time period.

In contrast, changes in ₂M mRNA and protein are regulated coordinately in CL of pregnant rats. ₂M mRNA is present, but in low concentration, from days 4–11 of gestation, increases markedly between days 11–21, and decreases at parturition, when functional luteolysis occurs. Hysterectomy of day 10 pregnant rats combined with hormone replacement determined that ₂M mRNA levels are regulated primarily by PRL through day 12 and by placental lactogens during midgestation (days 12–15). The increase in ₂M mRNA during pregnancy precedes the 40- fold increase (peak) in a ₂M protein observed on day 15, which remains elevated through day 21. These results demonstrate that ₂M mRNA and protein content are regulated in a tissue-specific manner in the rat ovary. In summary, the molecular mechanisms involved in regulating ₂M mRNA and protein in follicles and corpora lutea appear to differ. Although the intraovarian site of synthesis of ₂M in follicles is not yet clearly defined, ₂M mRNA and protein are produced by luteal cells during pregnancy in response to PRL (and placental lactogens).

Footnotes

^* This work was supported by NIH Grant AI-22166 (to G.H.F.) and NIH Grants HD-16272 and HD-16229 (to J.S.R.).

Received June 22, 1989.

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