Modulation of innate immunity by IL-18

IL-18 is expressed in various reproductive organs and its expression in the uterus fluctuates in linkage with menstrual cycle, implantation, pregnancy and delivery. However, the roles of this cytokine in reproduction remain obscure. IL-18 is a pleiotropic cytokine and exerts apparently complicated and sometimes paradoxical functions in immune and inflammatory responses, and a consensus understanding of its action has not been attained. Recent investigations reveal that IL-18 activates anti-apoptotic signals and promotes both survival and proliferation of activated lymphocytes as well as various cells exposed to different stressors. Especially, IL-18 enhances the expansion of NK and gammadelta T cells isolated from the circulation and stimulated in various ways. The expansion of gammadelta T cells, stimulated by zoledronate and IL-2, was strongly promoted by exogenous IL-18 and was inhibited by neutralizing anti-IL-18 receptor antibody. The expansion of gammadelta T cells was coincident with an increased number of CD11c+ cells. The gammadelta T cells that expanded in the presence of zoledronate, IL-2 and IL-18 exhibited the phenotype of effector memory cells characterized as CD44+ CD27- CD45RA- cells. In addition, they expressed NKG2D, perforin, CD94, CD25 and CD122, and 30-40% of them were positive for CD56. Incubation of expanded gammadelta T cells with IL-18 induced production of GM-CSF, IFNgamma and TNFalpha at much higher levels than those incubated without IL-18. They showed strong cytotoxicity against tumor cells, including mesothelioma cells, and inhibited growth of mesothelioma xenografts in mice. These observations suggest that IL-18 can efficiently promote expansion of gammadelta T cells with potent cytotoxicity.