The Tumor-Promoting Effect of TNF- Involves the Induction of Secretory Leukocyte Protease Inhibitor

According to the cancer immunoediting concept, inflammatory mediators play not only a critical role in promoting host protection against cancer but also contribute to cancer cell growth and survival. TNFis a critical factor in this network. However, the mechanisms underlying the tumor-promoting effect of TNFhave not been fully elucidated yet. We previously reported that in vitro culture of Lewis lung carcinoma 3LL cells with TNF-producing macrophages resulted in enhanced resistance toward TNF-mediated lysis and increased malignancy of the 3LL cells. In this study, we analyzed the effects of endogenous TNFon TNFresistance and malignant behavior in vivo of low-malignant/TNF-sensitive 3LL-S cells and cancer cells derived from 3LL-S tumors that developed in wild-type or TNF/ mice. Interestingly, 3LL-S cells acquired a malignant phenotype in vivo depending on the presence of host TNF, whereas acquisition of TNFresistance was TNF-independent. This result suggested that malignancy-promoting characteristics of 3LL-S cells other than TNFresistance are influenced in vivo by TNF. We previously identified the malignancy-promoting genes, secretory leukocyte protease inhibitor (SLPI) and S100A4, as being upregulated in 3LL-S cells upon their s.c. growth in wild-type mice. In this study, we show that SLPI, but not S100A4, was induced in 3LL-S cells both in vitro and in vivo by TNF, and that silencing of in vivo induced 3LL-S SLPI expression using RNA interference abrogated in vivo progression but did not influence TNFresistance. These data indicate that SLPI induction may be one mechanism whereby TNFacts as an endogenous tumor promoter. The Journal of Immunology, 2006, 177: 8046–8052.