Interleukin-1 Receptor Antagonist and Interleukin-1 beta: Different Roles in Patients with Chronic Lymphocytic Leukemia.

Interleukin-1 receptor antagonist (IL-1Ra) is a 23-KDa soluble glycoprotein that blocks the activity of IL-1α and IL-1β by competing with type I and type II IL-1 receptors without initiating signal transduction. IL-1Ra is anti-inflammatory, while IL-1β is a proinflammatory molecule. IL-1β enhances the immunological and hemopoietic systems and IL-1Ra acts as an inhibitor. IL-1β induces the cell surface expression of cytokine receptors on lymphoid and hemopoietic cells, whereas IL-1Ra suppresses this activity. IL-1β augments lymphoid and hemopoietic cell growth, whereas IL-1Ra suppresses this growth. We evaluated the clinical relevance of IL-1Ra and IL-1β levels in the plasma of 92 patients with chronic lymphocytic leukemia (CLL). IL-1Ra levels were significantly higher in CLL patients (median, 389, range 52–3667 pg/mL) than in 31 normal control subjects (median, 217; range, 94–868 pg/mL) (P <0.001). In contrast, IL-1B levels were significantly lower in CLL patients (median, 2.23; range, 1.89–12 pg/mL) than in normal controls (median, 2.68; range, 2.08–5.5) (P <0.01). Overall, neither IL-1Ra nor IL-1B correlated significantly with WBC count, β2-microglobulin (β2-M) level, Rai stage, platelet count, mutation status, or treatment history. Only age correlated with IL-1Ra (R = 0.39, P <0.001). Using a univariate Cox proportional hazards model, we found direct correlation with survival when IL-1Ra was used as a continuous variable (P <0.001). This association was independent of Rai stage, β-2M, and IgVH mutation status. However, in a multivariate analysis incorporating a combination of IgVH, β2-M, and IL-1Ra, IL-1Ra was no longer a predictor of survival. When patients were dichotomized according to the median IL-1Ra level, those with higher levels had longer survival (P = 0.057). In contrast, IL-1B did not correlate with survival (P = 0.14). These data suggest that IL-1Ra, but not IL-1B, plays a role in the biology of CLL and that the stronger the anti-inflammatory process in CLL, the more aggressive the disease.