The expression and role of IL-4 and IL-4(delta)2 in tuberculosis with and without HIV co-infection
Background: Tuberculosis progresses despite potent Thl responses. A putative explanation is the presence of a subversive Th2 response. However interpretation is confounded by a novel cytokine, IL-452, a splice variant and inhibitor of IL-4. Methods: The expression of Thl cytokines (IFN-y), IL-452, Th2 cytokines (IL-4) and sCD30 was investigated in whole blood, lung lavage and mononuclear cell cultures from donors with TB, TB-HIV co-infection, and matched controls. Results: After validation of a fluorogenic real-time RT-PCR assay, the half-life of IL- 4 mRNA, but not IL-452, was found to be prolonged in TB vs controls (P<0.002). mRNAs for IL-4 and IL-452 were elevated in unstimulated cells from blood and lung lavage of patients vs controls (p<0.005). Patients with TB expressed significantly greater mRNA levels of both cytokines in T-cells (p<0.05 compared to controls where expression was predominantly in non-T cells). Radiological disease correlated with the IL-4/IFN-y ratio and sCD30 (p<0.005). Tuberculosis antigen upregulated expression of IL-4 relative to IL-462 in mononuclear cell cultures from tuberculosis patients (P<0.05). By contrast, though HIV-TB co-infected donors had increased IL-4 in blood and lung lavage, in lung the predominant form was IL-452. After chemotherapy, in tuberculosis and in HIV-TB co-infection, IL-4 mRNA levels remained unchanged whilst IL-462 increased (p<0.05). Conclusions: A Th2-like response, prominent in T cells, and driven by TB antigen, is present in TB and is modulated by treatment suggesting a role for IL-4 and its antagonist, IL-452 in the pathogenesis of TB and their ratio as a possible marker of disease activity. Furthermore, enhancement of IL-4 mRNA stability, a hitherto undescribed regulatory mechanism in human TB, may facilitate the immunopathological effect of IL-4. The specific antigens inducing the IL-4 response require identification to facilitate future vaccine development strategies. Further studies are required to determine whether IL-4 facilitates systemic HIV progression in co-infected patients.