DNA-DAMAGING AGENTS INCREASE THE STABILITY OF INTERLEUKIN-1-ALPHA, INTERLEUKIN-1-BETA, AND INTERLEUKIN-6 TRANSCRIPTS AND THE PRODUCTION OF THE RELATIVE PROTEINS

In this study, we addressed the question of whether carcinogens affect ed the expression of interleukin-1 alpha (IL1 alpha), interleukin-1 be ta (IL1 beta), and interleukin-6 (IL6) genes and the production of the relative proteins. Primary cultures of human monocytes were exposed t o the alkylating agents mitomycin C (Mit C), methylmethane sulfonate ( MMS), and ethylmethane sulfonate (EMS) and tested for the production o f IL1 alpha, IL1 beta, and IL6 proteins, as well as for the expression of IL1 alpha, IL1 beta, and IL6 transcripts. The production of IL1 be ta and IL6 was significantly augmented by all the three chemicals afte r 24-48 h of treatment. IL1 alpha was also increased by Mit C and MMS. By Northern blotting analysis, the increased expression of IL1 alpha, IL1 beta, and IL6 genes was shown to occur at 30 min of Mit C and MMS treatment and to decline after 8 h. Similarly, EMS up-regulated the e xpression of IL1 beta and IL6 genes. The mutagen-mediated increase in interleukin transcripts did not require de novo protein synthesis, and it was due to the enhanced half-life of IL1 alpha, IL1 beta, and IL6 mRNAs rather than to the increased rate of gene transcription. These r esults suggest that carcinogens, in addition to causing DNA mutations and rearrangements, may also affect cell growth and differentiation by enhancing the expression of cytokine genes.