In vivo and in vitro studies of a novel cytokine, interleukin 4delta2, in pulmonary tuberculosis.
BACKGROUND
Tuberculosis progresses despite potent Th1 responses. A putative explanation is the simultaneous presence of a subversive Th2 response. However, interpretation is confounded by interleukin 4delta2 (IL-4delta2), a splice variant and inhibitor of IL-4.


OBJECTIVE
To study levels of mRNA encoding IL-4 and IL-4delta2, and their relationship to treatment and clinical parameters, in cells from lung lavage and blood from patients with pulmonary tuberculosis.


METHODS
IL-4delta2, IFN-gamma, 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-4delta2 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-4delta2 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/IFN-gamma ratio and sCD30 (p < 0.005). After chemotherapy, IL-4 mRNA levels remained unchanged, whereas IL-4delta2 increased in parallel with IFN-gamma (p < 0.05). Sonicates of Mycobacterium tuberculosis upregulated expression of IL-4 relative to IL-4delta2 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-4delta2 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.
Dheda
Keertan
K
Centre for Infectious Diseases and International Health, Royal Free and University College Medical School, 46 Cleveland Street, London W1T 4JF, United Kingdom.
Chang
Jung-Su
JS
Breen
Ronan A M
RA
Kim
Louise U
LU
Haddock
Jamanda A
JA
Huggett
Jim F
JF
Johnson
Margaret A
MA
Rook
Graham A W
GA
Zumla
Alimuddin
A
D000328:Adult; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016022:Case-Control Studies; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000276:immunology*; D008297:Male; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000276:immunology*
D012333:RNA, Messenger; D015847:Interleukin-4