INTERLEUKIN-1 RECEPTOR ANTAGONIST INHIBITS GROWTH MODULATION OF HUMANTUMOR-CELL LINES BY INTERLEUKIN-1 IN-VITRO

In this study we report that recombinant human (rh) interleukin-1alpha (IL-1alpha) has direct and dose-dependent growth-modulating effects o n human tumor cell lines in vitro as measured by a human tumor cloning assay (HTCA). Colony formation of the melanoma cell line A 375 was in hibited by rhIL-1alpha, whereas colony formation of the glioblastoma c ell line HTB 14 was enhanced by this cytokine. Both growth-modulating effects were dose-dependent, however with some saturation. Subsequentl y, we have tested the activity of recombinant human IL-1 receptor anta gonist (rhIL-1ra) on the tumor growth modulation by rhIL-1alpha. Tumor cells were incubated with increasing concentrations of rhIL-1ra and t hen added to the cultures containing rHIL-1alpha. Concentrations of rh IL-1ra were chosen to achieve a range between 0.01 and 100 ng/ml which includes a 1000-fold molar excess over IL-1alpha. The receptor antago nist was able to block both the inhibition and the stimulation of clon al growth of the respective tumor cell line by rhIL-1alpha. Furthermor e, there was a direct dose dependent relationship revealing higher IL- 1 antagonism of rhIL-1ra at higher concentrations with maximum efficac y at 1000-molar excess concentrations over IL-1alpha. In addition, rhI L-1ra alone did not reveal major modulation of the growth of A 375, bu t significantly decreased colony formation of HTB 14. We conclude that rhIL-1ra can counteract modulation of clonal growth of human tumor ce lls by IL-1alpha in vitro. Since our report provides first evidence th at the stimulation of clonal tumor cell growth by IL-1alpha can be blo cked by rhIL-1ra, this member of the IL-1 cytokine network should be f urther studied as a possible candidate for experimental cancer treatme nt.