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

Research output: Contribution to journalArticle

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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

Fingerprint

Interleukins
Pulmonary Tuberculosis
Interleukin-4
Cytokines
Tuberculosis
Messenger RNA
Bronchoalveolar Lavage
Antigens
In Vitro Techniques
Mycobacterium tuberculosis
Immunoassay
Blood Cells
Vaccines
Cell Culture Techniques
T-Lymphocytes
Drug Therapy
Polymerase Chain Reaction

Keywords

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

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

In vivo and in vitro studies of a novel cytokine, interleukin 4δ2, in pulmonary tuberculosis. / Dheda, Keertan; Chang, Jung Su; Breen, Ronan A M; Kim, Louise U.; Haddock, Jamanda A.; Huggett, Jim F.; Johnson, Margaret A.; Rook, Graham A W; Zumla, Alimuddin.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 172, No. 4, 15.08.2005, p. 501-508.

Research output: Contribution to journalArticle

Dheda, Keertan ; Chang, Jung Su ; Breen, Ronan A M ; Kim, Louise U. ; Haddock, Jamanda A. ; Huggett, Jim F. ; Johnson, Margaret A. ; Rook, Graham A W ; Zumla, Alimuddin. / In vivo and in vitro studies of a novel cytokine, interleukin 4δ2, in pulmonary tuberculosis. In: American Journal of Respiratory and Critical Care Medicine. 2005 ; Vol. 172, No. 4. pp. 501-508.
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AU - Chang, Jung Su

AU - Breen, Ronan A M

AU - Kim, Louise U.

AU - Haddock, Jamanda A.

AU - Huggett, Jim F.

AU - Johnson, Margaret A.

AU - Rook, Graham A W

AU - Zumla, Alimuddin

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N2 - 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.

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