REGULATION OF MONOCYTE-DERIVED INTERLEUKIN-1 RECEPTOR ANTAGONIST BY CISPLATINUM

IL-1 biology has taken on a new dimension with the discovery of the IL-1 receptor antagonist (IL-1ra). The balance in the production of monocyte-derived IL-1 and IL-1ra may impact on subsequent IL-l-dependent inflammation, Cancer patients are known to have impaired monocyte biological function, Interestingly, cancer patients receiving chemotherapeutic I regiments containing cisplatinum appear to regain enhanced monocyte cytolytic activity both in vitro and in vivo, We postulated that cisplatinum may enhance the normal biological function of monocytes via its effect on IL-1. biology. Monocytes isolated from normal healthy subjects cultured in the presence of graded concentrations of cisplatinum with or without lipopolysaccharide (LPS) demonstrated significantly attenuated production of monocyte-derived IL-1ra in a dose-dependent manner. Moreover, the delayed addition of cisplatinum to monocyte cultures (up to 4 h), in relation to LPS stimulation, significantly suppressed IL-1ra protein by 49%, The level of this regulation was inhibition of IL-1ra mRNA. In contrast, cisplatinum failed to significantly inhibit the production of monocyte-derived IL-1 beta or other pro-inflammatory cytokines. These findings support the notion that cisplatinum has disparate effects on monocyte-derived cytokines, and provide a potential mechanism for cisplatinum's effects on monocyte function in cancer patients.