CD40 ligand-CD40 interaction induces chemokines in cervical carcinoma cells in synergism with IFN-gamma

Cellular immunity plays a major role in controlling human papilloma virus i nfection and development of cervical carcinoma. Mononuclear cell infiltrati on possibly due to the action of chemokines becomes prominent in the tumor tissue. In fact, the macrophage chemoattractant protein-1, MP-1, was detect ed in cervical squamous cell carcinoma in situ, whereas absent in cultured cells, From this, unknown environmental factors were postulated regulating chemokine expression in vivo. In this study, we show high CD40 expression o n cervical carcinoma cells and CD40 ligand (CD40L) staining on attracted T cells in tumor tissue, suggesting a paracrine stimulation mechanism via CD4 0L-CD40 interactions. We therefore investigated chemokine synthesis in nonm alignant and malignant human papilloma virus-positive cell lines after CD40 L exposure, Constitutive expression of MCP-I, MCP-3, RANTES, and IFN-gamma- inducible protein-10 was almost undetectable in all cell lines tested. CD40 L was able to induce MCP-1 production; however, despite much higher CD40 ex pression in malignant cells, MCP-1 induction was significantly lower compar ed with nontumorigenic cells. After sensitization with IFN-gamma, another T cell-derived cytokine showing minimal effects on CD40 expression levels, C D40 ligation led to a more than 20-foId MCP-1 induction in carcinoma cell l ines. An even stronger effect was observed for IFN-gamma-inducibte protein- 10., Our study highlights the synergism of T cell-derived mediators such as CD40L and IFN-gamma for chemokine responses in cervical carcinoma cells, h elping to understand the chemokine expression patterns observed in vice.