In vivo and in vitro studies of a novel cytokine, interleukin 4δ2, in pulmonary tuberculosis

Keertan Dheda, Jung Su Chang, Ronan A M Breen, Louise U. Kim, Jamanda A. Haddock, Jim F. Huggett, Margaret A. Johnson, Graham A W Rook, Alimuddin Zumla

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60 Citations (Scopus)

Abstract

Rationale: Tuberculosis progresses despite potent Th1 responses. A putative explanation is the simultaneous presence of a subversive Th2 response. However, interpretation is confounded by interleukin 4δ2 (IL-4δ2), a splice variant and inhibitor of IL-4. Objective: To study levels of mRNA encoding IL-4 and IL-482, and their relationship to treatment and clinical parameters, in cells from lung lavage and blood from patients with pulmonary tuberculosis. Methods: IL-482, IFN-γ, IL-4, and soluble CD30 (sCD30) levels were measured by polymerase chain reaction and relevant immunoassays in 29 patients and matched control subjects lacking responses to tuberculosis-specific antigens. Results: mRNA levels for IL-4 and IL-4δ2 were elevated in unstimulated cells from blood and lung lavage of patients versus control subjects (p <0.005). In control subjects, there were low basal levels of IL-4 and IL-4δ2 mRNA expressed mainly by non-T cells (p <0.05). However, in patients, there were greater levels of mRNA for both cytokines in both T- and non-T-cell populations (p <0.05 compared with control subjects). Radiologic disease correlated with the IL-4/INF-γ ratio and sCD30 (p <0.005). After chemotherapy, IL-4 mRNA levels remained unchanged, whereas IL-4δ2 increased in parallel with IFN-γ (p <0.05). Sonicates of Mycobacterium tuberculosis upregulated expression of IL-4 relative to IL-4δ2 in mononuclear cell cultures from patients (p <0.05). Conclusions: A Th2-like response, prominent in T cells and driven by tuberculosis antigen, is present in tuberculosis and modulated by treatment, suggesting a role for IL-4 and IL-482 in the pathogenesis of tuberculosis and their ratio as a possible marker of disease activity. The specific antigens inducing the IL-4 response require identification to facilitate future vaccine development strategies.

Original languageEnglish
Pages (from-to)501-508
Number of pages8
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume172
Issue number4
DOIs
Publication statusPublished - Aug 15 2005
Externally publishedYes

Keywords

  • Cytokines
  • Human
  • Interleukin 4
  • Th1/Th2 cells
  • Tuberculosis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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    Dheda, K., Chang, J. S., Breen, R. A. M., Kim, L. U., Haddock, J. A., Huggett, J. F., Johnson, M. A., Rook, G. A. W., & Zumla, A. (2005). In vivo and in vitro studies of a novel cytokine, interleukin 4δ2, in pulmonary tuberculosis. American Journal of Respiratory and Critical Care Medicine, 172(4), 501-508. https://doi.org/10.1164/rccm.200502-278OC