Downregulation of macrophage IL-12 production by tumor-derived IL-11

We have previously shown that macrophages from mammary tumor-bearing mice have a profound downregulation of IL-12, which has been implicated in the low levels of IFN-γ and generally depressed lymphoreticular cells functions in this tumor model. The tumor used in our studies constitutively produces several factors that have immunosuppressive activity (ie granulocyte macrophage-colony stimulating factor [GM-CSF], prostaglandin E₂ [PGE₂], and phosphatidyl serine [PS]). Of these factors, PGE₂ and PS have been shown to exert effects on macrophage functions. Recently, we found that these tumor cells express IL-11 at both the transcriptional and translational levels, as evidenced by RT-PCR and by Western blots. Treatment of normal macrophages with IL-11 resulted in a downregulation of IL-12. In further studies using a murine IL-11 ELISA, we observed low constitutive levels of this cytokine in the supernatants of macrophage cultures from normal mice, which is upregulated upon stimulation with LPS. Importantly, macrophages from tumor bearers have higher production of IL-11 than their normal counterparts. Our results suggest that tumor cell derived IL-11, in conjunction with the elevated levels of this cytokine in tumor-bearing animal macrophages, play a role in the depressed IL-12 production, leading to the impaired immune functions observed during mammary tumorigenesis.