IL-6 Mediates 11βHSD Type 2 to Effect Progression of the Mycobacterial Cord Factor Trehalose 6,6′-Dimycolate-Induced Granulomatous Response

Abstract

Granulomatous structures are highly dynamic during active mycobacterial infection, with accompanying responsive inflammation contributing to modulation of pathology throughout the course of disease. The heightened inflammatory response coinciding with initiation and maintenance of newly developing granulomatous structures must be limited to avoid excessive damage to bystander tissue. Modulating the cellular bioavailability of glucocorticoids by local regulation of 11βHSD enzymes within responding tissue and parenchyma would allow controlled inflammatory response during infection. Mycobacterial glycolipid trehalose 6,6′-dimycolate was used to induce strong pulmonary granulomatous inflammation immunopathology. Pulmonary corticosterone was significantly increased at days 3 and 5 after administration. An inverse relationship of 11βHSD1 and 11βHSD2 message correlated with pathology development. Immunohistochemical analysis also demonstrated that 11βHSD2 is expressed in proximity to granulomatous lesions. A role for pro-inflammatory IL-6 cytokine in regulation of converting enzymes to control the granulomatous response was confirmed using gene-disrupted IL-6–/– mice. A model is proposed linking IL-6 to endocrine-derived factors which allows modification of active corticosterone into inert 11-dehydrocorticosterone at the site of granuloma formation to limit excessive parenchymal damage.

Genetic variations in the SPP1 promoter affect gene expression and the level of osteopontin secretion into bovine milk

“…The ability to mount and sustain a mycobacteria‐induced granulomatous response is severely compromised by IL6 deficiency (Abbott et al . ). It was thus interesting to observe that SPP1 genetics influenced both SPP1 and IL6 expressions.…”

Lactoferrin: A Modulator for Immunity against Tuberculosis Related Granulomatous Pathology

“…Using knockout mice, established patterns of cytokine production were found to be associated with pathology. This allowed the delineation of the major molecular events in innate establishment and maintenance of the TDM induced granuloma [ 17 , 33 , 37 , 38 , 41 , 52 – 56 ]. A link was also established to adaptive (T-cell mediated) hypersensitive responses critical for development of pathological granulomas [ 57 , 58 ] ( Figure 1 ).…”

Mycobacterial trehalose 6,6′-dimycolate induced vascular occlusion is accompanied by subendothelial inflammation

“…The TDM in oil formulation was intraperitoneally (IP) delivered. The TDM oil/water emulsion was prepared as previously described 14 . Briefly, evaporated TDM (10 or 25 μg/mouse) was homogenized in Drakeol (2 μL/mouse), 48 μL/mouse of 1x DPBS (Dulbeccos' Phosphate Buffered Solution, Cellgro) with 0.2% Tween 80 (Mallinckrodt, Hazelwood, MO) was added and homongenized.…”

“…However, in hindsight, the model had been adapted to intravenous administration of TDM to promote a synchronized transient granulomatous response. While this allowed assessment of factors involved in development of the granuloma [12][13][14] , the model no longer accurately represented events during primary tuberculosis infection in which pulmonary hemorrhage occurs.…”