Effect of IL-1beta secretion on lymphoid tissue and on antitumor immune responses

Sammanfattning: Interleukin (IL)-1beta is one of the most pleiotropic and potent cytokines, produced predominantly by activated monocytes and macrophages. IL-1 plays an important role in normal immunoregulatory processes but also in pathophysiological inflammatory responses. In the present study, we developed a model for active IL-1beta secretion. A retroviral vector containing a cDNA construct encoding the mature form of IL-1b, fused to a signal sequence (ssIL-1beta), was used to transduce target cells. Analysis of cell lysates and supernatants of the transfected target cells showed that the addition of a signal sequence resulted in high extracellular release of the protein, whereas the protein retained intracellularly if the signal sequence was absent. We further evaluated how local and active release of IL-1beta from tumor cells influenced an antitumor immune response against the poorly immunogenic murine B16 melanoma. We showed that the in vivo tumor growth of IL-1beta-transduced tumor cells was significantly reduced when IL-1beta was locally secreted in the tumor area. The tumor growth inhibition correlated with infiltration of macrophages, CD4+ T cells and dendritic cells. We further demonstrated that vaccination with irradiated IL-1beta-secreting tumor cells, stimulated a T cell dependent, long lasting anti-tumor immunity against the wild type B16F10 tumor. In contrast, nontransduced irradiated tumor cells possessed little or no ability to stimulate systemic antitumor immunity. To evaluate the biological effect of over-expression of IL-1beta in lymphoid tissue, we further generated transgenic mice that expressed the ssIL-1b gene construct under the control of a mouse immunoglobulin enhancer. We found that these mice developed a number of abnormal features such as lymphoid hyperplasia, aberrant architecture of lymphoid organs, hypergammaglobulinemia and appearance of activated CD4+ T cells. In conclusion, IL-1beta may be therapeutically useful to augment antitumor immune responses, when locally secreted during the vaccination phase. However, demonstrated by our transgenic model, IL-1beta might in a more chronic setting lead to pathological conditions such as unregulated proliferation and activation of lymphocytes.