Interleukins 1alpha and 1beta secreted by some melanoma cell lines strongly reduce expression of MITF-M and melanocyte differentiation antigens.
We report that melanoma cell lines expressing the interleukin-1 receptor exhibit 4- to 10-fold lower levels of mRNA of microphthalmia-associated transcription factor (MITF-M) when treated with interleukin-1beta. This effect is NF-kappaB and JNK-dependent. MITF-M regulates the expression of melanocyte differentiation genes such as MLANA, tyrosinase and gp100, which encode antigens recognized on melanoma cells by autologous cytolytic T lymphocytes. Accordingly, treating some melanoma cells with IL-1beta reduced by 40-100% their ability to activate such antimelanoma cytolytic T lymphocytes. Finally, we observed large amounts of biologically active IL-1alpha or IL-1beta secreted by two melanoma cell lines that did not express MITF-M, suggesting an autocrine MITF-M downregulation. We estimate that approximately 13% of melanoma cell lines are MITF-M-negative and secrete IL-1 cytokines. These results indicate that the repression of melanocyte-differentiation genes by IL-1 produced by stromal cells or by tumor cells themselves may represent an additional mechanism of melanoma immune escape.
Kholmanskikh
Olga
O
Ludwig Institute for Cancer Research Ltd, Brussels branch, and Université Catholique de Louvain, 74 avenue Hippocrate, UCL7459, B1200 Brussels, Belgium.
van Baren
Nicolas
N
Brasseur
Francis
F
Ottaviani
Sabrina
S
Vanacker
Julie
J
Arts
Nathalie
N
van der Bruggen
Pierre
P
Coulie
Pierre
P
De Plaen
Etienne
E
D002454:Cell Differentiation; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053582:Interleukin-1alpha / Q000378:metabolism / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology* / Q000276:immunology; D008545:Melanoma / Q000235:genetics / Q000276:immunology*; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics*; D016328:NF-kappa B / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D016207:Cytokines; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D051739:Microphthalmia-Associated Transcription Factor; D016328:NF-kappa B; D012333:RNA, Messenger; D048670:MAP Kinase Kinase 4