Constitutive Aberrant Endogenous Interleukin-1 Facilitates Inflammation and Growth in Human Melanoma

Interleukin (IL)-1-mediated inflammation is proposed to contribute to the development and progression of some cancers. IL-1 family member proteins are known to be expressed constitutively in many melanoma tumor cells, and we hypothesize that these support molecular pathways of inflammation and facilitate tumor growth. To investigate the expression of IL-1 alpha and IL-1 beta in melanoma patients, and their association with disease progression, immunohistochemical staining was carried out on tissues from 170 patients including benign nevi, primary melanomas, and metastatic melanomas. IL-1 beta levels were low (or zero) in benign nevi and higher in primary and metastatic melanomas (P < 0.0001). IL-1 alpha was expressed in about 73% of nevi and 55% of metastatic melanomas, with levels significantly higher in primary tumors (P < 0.0001); most (98%) primary melanoma samples were positive for IL-1 alpha. In vitro studies with seven human melanoma cell lines showed that five cell lines expressed IL-1 alpha and IL-1 beta proteins and mRNA. We identified for the first time several important downstream signaling pathways affected by endogenous IL-1, including reactive oxygen and nitrogen species, COX-2, and phosphorylated NF-kappa B inhibitor (I kappa B) and stress-activated protein kinase/c-jun-NH2-kinase; all of which were decreased by siRNA to IL-1s. Downregulation of IL-1 alpha, IL-1 beta, or MyD88 substantially increased p21 and p53 levels. Treatment with IL-1 receptor type I neutralizing antibody or IL-1 pathway-specific siRNAs led to growth arrest in IL-1-positive melanoma cells. Furthermore, blocking the IL-1 pathway increased autophagy in IL-1-positive melanoma cells. These results indicate that the endogenous IL-1 system is functional in most human melanoma and interrupting its signaling inhibits the growth of IL-1-positive melanoma cells. Mol Cancer Res; 9(11); 1537-50. (C) 2011 AACR.