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

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.

Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

“…MMP-12, in particular, plays an essential role in smokeinduced emphysema in mice [65] and activates proTNF in macrophages [66]. It remains to be investigated whether the reduced toxicity of TNF-a observed in M. tuberculosis-infected IL-4 -/-mice is related at least in part to reduced MMP-12 expression [21].…”

“…[20]. Reduced bacterial growth in the lungs of IL-4 -/-mice on the Balb/c background, altered histopathology, and delayed-type hypersensitivity responses indicate a suppressive effect of IL-4 on the Th1 response [21]. Accumulating evidence thus suggests that M. tuberculosis promotes an environment characterized by Th2 cytokines during infection.…”

The Pathology ofMycobacterium tuberculosisInfection

“…92 TGF-b is also associated with fibrosis during chronic Mtb infection. 97 IL-27, a member of the IL-12 cytokine family, has been shown to negatively regulate development of Th17-type cells during chronic inflammation. 194 Improved control of mycobacterial growth due to increased inflammatory cytokine responses in the lungs of mice lacking IL-27 receptor signaling has been reported.…”

Expression of apoptosis‐related genes in an Ethiopian cohort study correlates with tuberculosis clinical status

“…However, it has been suggested that soluble TNFR does not fully explain the effects of TNF-a inhibitors on M. tuberculosis [34,35], and so work into other virulence factors is ongoing. Recent results also suggests that IL-4 (which is associated with poor outcome in human TB) [19] may promote necrosis over apoptosis in M. tuberculosis-infected macrophages (Abebe et al, unpublished data) providing a potential explanation of the observed link between TNF-a, IL-4 and pathological changes [36,37].…”

“…However, it has been suggested that soluble TNFR does not fully explain the effects of TNF-a inhibitors on M. tuberculosis [34,35], and so work into other virulence factors is ongoing. Recent results also suggests that IL-4 (which is associated with poor outcome in human TB) [19] may promote necrosis over apoptosis in M. tuberculosis-infected macrophages (Abebe et al, unpublished data) providing a potential explanation of the observed link between TNF-a, IL-4 and pathological changes [36,37].The goal of this study was therefore to observe what, if any, changes occurred during human TB in the expression of genes for the so-called ''death receptor'' complexes (Fas, FasL, TNF-a and the TNFR1 and TNFR2 receptors), which led to activation of the apoptotic cascade via the Fas-associated death domain protein (FADD) and the pro-apoptotic molecule Caspase 8. We have used RT-PCR to compare the expression of these genes in the peripheral blood of sputum-positive TB patients, their close household contacts and healthy community controls (CC) from Ethiopia, a TB-endemic country.…”