Recombinant Expression Of Interleukin-18 And Its Antitumor Effects

The list of mterleukins is growing at a steady rate. Although, it is over 8 yearssince the initial description of interferon gamma inducing factor (IGIF, now calledIL- 18), this novel cytokine is still not well characterised. However, the data weresufficient to support the testing of IL- 18 in experimental tumour therapy. IL- 18 isproduced mainly by macrophages. Similarly to IL-lbeta, IL-18 does not possess asignal sequence allowing direct secretion through the plasma membrane. Although,the exact mechanism of IL- 18 secretion is not confirmed, it seems that, like IL-lbeta, IGIF is processed by the cysteine proteases belonging to caspase family,especially by ICE (interleukin lbeta converting enzyme). Among the target cellsresponding to IL- 18 are T lymphocytes and NK cells, which, under the influence ofIL- 18, produce substantial amounts of IFN-gamma. In this respect IL- 18 seems tobe even stronger than IL-12. Similarly to IL-l2, IL-18 stimulates cytotoxicity of Tand NK cells. Moreover, it enhances FasL-mediated cytotoxicity of CD4+ T andNK cells. A potential role of IL- 18 in tumour immunotherapy is discussed in thisarticle with special emphasis on the similarities with IL- 12 and the potentialmechanisms of its antituniour activity in preclinical models in mice.Interleukin- 18 (interferon--inducing factor/IL-i) has a wide range ofimmunoregulatory functions, including stimulation of interferon- production,induction of natural killer (NK) cell cytotoxicity, potentiation ofThl differentiation,and inhibition of osteoclast proliferation. IL-18-deficient mice display a phenotypelargely similar to that of IL- 12 knockout mice, exhibiting reductions in interferon-~yproduction, NK cell activity, and Thl response. Interestingly, IL-18 and IL-l2double-deficient mice displayed an even greater perturbation of NK cell activityand Th1 cell response than that seen in either of the single knockouts. In terms ofits biological effects, IL- 18 is thus closely related to and acts synergistically withIL- 12. Analysis of amino acid sequence and structural motifs, however, classify' IL-18 as a member of the IL-i family of cytokines. In agreement with this6(i8~Bf~ ~classification, IL- 18 has been shown to be processed by the interleukin- 1-converting enzyme, which also processes IL-i. Furthermore, IL- 18 signaling wasshown to be mediated by a member of the IL-1R family, IL-LR-rp. It was alsorecently shown that IL- 18 can activate IRAK, recruit TRAF6, and inducetranslocation of NFB, which are all involved in IL-i signaling.IL-18R is selectively and persistently expressed on Thl but not Tb2 cells. Thus,IL-18R not only serves as a cell surface marker distinguishing Thl from Th2 cells,but also provides an explanation for the selective biological effect of IL-18. Inaddition, our data provide a mechanism by which IL-18 synergizes with IL-12 inthe expansion of Th 1 cells through reciprocal modification of receptor expression,leading directly to enhanced production of IFN-y. The persistent expression of IL-18R on Thl cells suggests that IL-18 may play a dominant role in Thl expansionand function. Furthermore, antibody against IL-18R affects Thl functions in vitroand invivo.IL- 18 is produced by monocytic cells after pathogenic infections . Since IL-1 8R is selectively present on a distinct subset of T cells, IL- 18 likely plays animportant role beyond providing a link between innate and adaptive immuneresponse. The ability of IL- 18 to support Thl expansion is determined by theselective expression of IL-18R on Thl cells. Therefore, it would be of considerableinterest to determine the mechanism whereby IL-i 8R is preferentially expressed onThl but not Th2 cells during their dichotomous development from a commonprecursor. However, since NK...