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J. Biol. Chem., Vol. 279, Issue 53, 55297-55307, December 31, 2004

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Inhibition of Cytotrophoblastic (JEG-3) Cell Invasion by Interleukin 12 Involves an Interferon -mediated Pathway^*

Subhradip Karmakar, Ruby Dhar¶, and Chandana Das

From the Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India

Trophoblast invasion, like tumor invasion, shares common biochemical mechanisms. However, in contrast to tumor invasion of a host tissue, trophoblastic invasion during implantation is strictly regulated, temporospatially. Factors responsible for these important regulatory processes are presently unknown; however, studies indicate that cytokines and growth factors represent in the peri-implantation uterine milieu as the possible candidates. In this study we investigated the role of interleukin (IL) 12 in regulating trophoblast invasion and the expression of trophoblast proteases (matrix metalloprotease (MMP)-2, MMP-9, and urokinase-type plasminogen activators) and their inhibitors (tissue inhibitors of metalloprotease (TIMP) 1, TIMP-2, and plasminogen activator inhibitor (PAI)-1) using an in vitro tissue culture system of human choriocarcinoma cell line JEG-3. Our major findings show an anti-invasive role of IL-12, associated with an inhibitory effect on the proteases but with an opposite up-regulating influence on the protease inhibitor, TIMP-1, whereas TIMP-2 and plasminogen activator inhibitor 1 remained unaltered. Stimulation of JEG-3 cells with IL-12 also induced interferon (IFN)- production, which when neutralized using a monoclonal anti-IFN- antibody, F12, abrogates its ability to down-regulate the MMPs. IL-12 also mediates an IFN--dependent up-regulation of E-cadherin, thereby implying that alteration in cell-cell adhesion besides regulating the proteases and the inhibitors possibly contributes to the observed anti-invasive role of this cytokine. TIMP-1, although stimulated by IL-12, was found to be unaltered by antibody F12, thereby implying a possibility of an IL-12-dependent-IFN- independent regulation. These findings thereby suggest an important role of IL-12 in modulation of trophoblast proteases and their inhibitors besides regulating cell-cell interactions and invasion during implantation, with far reaching possibilities for understanding the mechanism(s) and regulations of invasion and metastasis.

Received for publication, June 23, 2004 , and in revised form, September 8, 2004.

^* This work was supported in part by a research grant from Indian Council of Medical Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^¶ Supported by a Council of Scientific and Industrial Research, New Delhi, India research fellowship.

To whom correspondence should be addressed: Dept. of Biochemistry, Rm. 3024. All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029, India. Tel.: 91-11-26594483; Fax: 91-11-26588641 or 91-11-26588663; E-mail: subhradipaiims{at}hotmail.com.

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