Pulmonary tuberculosis in BALB/c mice with non‐functional IL‐4 genes: changes in the inflammatory effects of TNF‐α and in the regulation of fibrosis

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Abstract
In BALB/c mice, as in man, progressive pulmonary tuberculosis is accompanied by increasing expression of IL‐4. Therefore we have used BALB/c mice with disrupted IL‐4 genes (IL‐4–/–) to investigate the role of IL‐4 in pulmonary tuberculosis, with particular emphasis on the toxicity of TNF‐α and on fibrosis, both of which are neglected aspects of human tuberculosis. Delayed‐type hypersensitivity (DTH) sites in IL‐4+/+ mice were sensitive to the toxicity of locally injected TNF‐α, whereas DTH sites in IL‐4–/– mice were not. However, intravenous administration of IL‐4 to IL–4–/– mice restored the sensitivity of the DTH sites to pro‐inflammatory effects of TNF‐α. In late disease, the lungs of IL‐4+/+ mice expressed low IFN‐γ, but high TGF‐β and IL‐4, correlating with fibrosis, detected as a high hydroxyproline content. In contrast, TGF–β peaked 7 days after infection in the lungs of the IL‐4–/– mice, and then fell to very low levels in the late disease, while IFN‐γ remained high. Accordingly, hydroxyproline content was reduced in infected IL‐4–/– mice compared to IL‐4+/+ controls. In conclusion, the findings suggest that IL‐4 has modestly detrimental effects on the antibacterial efficacy of the Th1 response, and larger effects on the toxicity of TNF‐α, and on fibrosis.

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