IL-1 and pro-inflammatory cytokines produced by primary and transformed fibroblasts abrogate the tumorigenic potential of fibrosarcomas.

In the present study we report on novel immunoregulatory functions lately attributed to fibroblasts, namely participation in cellular immune responses in connective tissues, by generation of pro-inflammatory cytokines and by presenting antigens to proliferating T cells. In order to execute immunoregulatory functions, the fibroblast has to be activated by signals abundant at inflammatory sites, i.e., cytokines and bacterial products. It was demonstrated that such immune-activated fibroblasts are able to generate a variety of cytokines such as interleukin-1 (IL-1), IL-6, colony stimulating factors (CSFs) as well as prostaglandins. The array of cytokines generated by immune-activated fibroblasts is determined by the stimulant and is controlled at multiple regulatory levels, such as transcription, translation, post-translational modifications, compartmentalization within the producing cell as well as the timing of expression. Some oncogene-transformed fibroblastoid cells lines were shown to constitutively generate IL-1 (and not IL-1 beta), as evidenced by the continuous expression of specific mRNA and biological activity of the cytokine, associated to the cell membrane or located in the cytosol. When these IL-2 producing cell lines were injected into mice, they failed to generate established tumors or regressed following initial growth, possibly due to mounting the host anti-tumor specific immune responses in which cytotoxic lymphocytes (CTLs) predominate. In contrast, IL-1 non-producing tumor cell lines induced progressive tumors which ultimately killed the animals. However, IL-1 non-producing fibroblastoid cell lines shifted from an in vivo progressive to a regressive phenotype, following immune activation of the malignant cells in vitro with cytokines/LPS. Similarly, primary immune-activated fibroblasts also induced tumor regression, mediated by anti-tumor specific immune responses, when the fibroblasts were injected into the vicinity of the tumor. Thus, the importance of activated stromal cells on tumor development was emphasized. This situation is relevant to the development of malignancies, as tumor growth is often accompanied by a local inflammatory response. Thus, the induction of IL-1 and other pro-inflammatory cytokines expression by the malignant cells or by stromal cells, in the vicinity of the tumor, might be efficient for tumor eradication. These findings should serve as a basis for development of novel immunotherapeutical strategies for the eradication of solid tumors.