Lactoferrin modulation of mycobacterial cord factor trehalose 6-6'-dimycolate induced granulomatous response

The immune system responds to tuberculosis (TB) infection by forming granulomas. However, subsequent immune-mediated destruction of lung tissue is a cause of significant morbidity and contributes to disease transmission. Lactoferrin, an iron-binding glycoprotein, has demonstrated immunomodulatory properties that decrease tissue destruction and promote T_H1 immune responses, both of which are essential for controlling TB infection. The cord factor trehalose 6,6'-dimycolate (TDM) model of granuloma formation mimics many aspects of TB infection with a similar histopathology accompanied by proinflammatory cytokine production. C57BL/6 mice were injected intravenously with TDM. A subset of mice was given 1 mg of bovine lactoferrin 24 h post-TDM challenge. Lung tissue was analyzed for histological response and for the production of proinflammatory mediators. C57BL/6 mice demonstrated a granuloma formation that correlated with an increased production of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α,) IL-12p40, interferon-gamma (IFN-γ), and IL-10 protein. Mice treated with lactoferrin postchallenge had significantly fewer and smaller granulomas compared with those given TDM alone. Proinflammatory and T_H1 cytokines essential to the control of mycobacterial infections, such as TNF-α and IFN-γ, were not significantly different in mice treated with lactoferrin. Furthermore, the anti-inflammatory cytokines IL-10 and transforming growth factor-β were increased. A potential mechanism for decreased tissue damage observed in the lactoferrin-treated mice is proposed. Because of its influence to modulate immune responses, lactoferrin may be a useful adjunct in the treatment of granulomatous inflammation occurring during mycobacterial infection.

Abbreviations: BCG, Bacille Calmette Guerin, BMM, bone marrow-derived macrophages, BSA, bovine serum albumin, DMEM, Dulbecco's modified Eagle's medium, ELISA, enzyme-linked immunosorbent assay, FBS, fetal bovine serum, GM-CSF, granulocyte/macrophage colony stimulating factor, HIV, human immunodeficiency virus, IFN-γ, interferon-gamma, IL, interleukin, LPS, lipopolysaccharide, MOI, multiplicity of infection, MTB, Mycobacterium tuberculosis, PBS, phosphate buffered saline, TB, tuberculosis, TDM, trehalose 6,6'-dimycolate, TGF-β, transforming growth factor, TNF-α, tumor necrosis factor α