Primary Hepatocytes from Mice Treated with IL-2/IL-12 Produce T Cell Chemoattractant Activity that Is Dependent on Monokine Induced by IFN-γ (Mig) and Chemokine Responsive to γ-2 (Crg-2)

Abstract

The IFN-γ-inducible proteins monokine induced by IFN-γ (Mig) and chemokine responsive to γ-2 (Crg-2) can contribute to IL-12-induced antiangiogenic and leukocyte-recruiting activities, but the extent to which leukocytes vs parenchymal cells in different organs contribute to the production of these molecules remains unclear. The results presented herein show that IFN-γ-dependent induction of Mig and Crg-2 gene expression can occur in many nonlymphoid organs, and these genes are rapidly induced in purified hepatocytes isolated from mice treated with IL-2 plus IL-12, or from Hepa 1-6 hepatoma cells treated in vitro with IFN-γ. In addition to depending on IFN-γ, the ability of IL-12 or IL-2/IL-12 to induce Mig and Crg-2 gene expression in purified hepatocytes also is accompanied by the coordinate up-regulation of the IFN-γ R α and β-chains, in the absence of IL-12R components. Supernatants of primary hepatocytes obtained from mice treated in vivo with IL-2/IL-12 or from hepatocytes treated in vitro with IFN-γ contain increased chemotactic activity for enriched human and mouse CD3+ T cells, as well as mouse DX5+ NK cells. The hepatocyte-derived chemotactic activity for mouse T cells but not NK cells was ablated by Abs specific for Mig and Crg-2. These results suggest that parenchymal cells in some organs may contribute substantially to initiation and/or amplification of inflammatory or antitumor responses.

Interleukins-12 and -23 Do Not Alter Expression or Activity of Multiple Cytochrome P450 Enzymes in Cryopreserved Human Hepatocytes

“…The IL-23 expression data are consistent with recent observations by R. Evers from Merck and Co. (unpublished observations), who observed negligible expression of IL-23R in cultured human hepatocytes. Lack of significant IL-12Rb1 and IL-12Rb2 expression was also demonstrated previously in mouse hepatocytes (Park et al, 2001). This is the first study to report the absence of significant levels of IL-12Rb1 and IL-12Rb2 expression in cultured human hepatocytes.…”

Expression of the CXCR3 ligand I-TAC by hepatocytes in chronic hepatitis C and its correlation with hepatic inflammation

“…25 Adenovirus-induced hepatitis in mice 26 results in hepatocyte expression of IP-10 and Mig and is essential for T cell recruitment, while hepatocytes isolated in vitro from mice injected with IL-12 and IL-2 produce IP-10 and Mig via an IFN-␥-dependent pathway. 27 Recent reports have also demonstrated IP-10 and Mig expression in CHC that correlates with inflammation. 13,14 Consistent with these observations, we show in this study that I-TAC is strongly and consistently upregulated at the mRNA and protein level in CHC and that mRNA expression levels correlate with liver histology, particularly portal and lobular inflammation.…”

IFN-γ and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy

“…Total cellular RNA was isolated from snapfrozen tissue specimens by the Trizol method. Reverse transcription and PCR reactions were performed consistent with methods we have described previously (13,21).…”