The Yin-Yang of TNFα in the guinea pig model of tuberculosis

Tumour necrosis factor alpha (TNF-α) is a prototypic pro-inflammatory cytokine that has a central role in the initial host response to Mycobacterium tuberculosis infection. It is a key player in granuloma formation, macrophage activation, bacterial killing, and pathology in vivo. However, the exact mechanism has not been completely understood. This review summarizes the TNFα data acquired from the ‘gold standard’ guinea pig animal model of tuberculosis. While production of TNFα is widely accepted as beneficial to the host response, we have found that this hypothesis is just one side of the story. TNFα can up-regulate and down-regulate some key pro-inflammatory cytokines (IFNγ, IL-12p40) and differentially modulate macrophage activation and intracellular bacterial growth. Neutralization of TNFα in vivo allows an antiinflammatory TGFβ-mediated response to develop. Furthermore, BCG vaccination modulates TNFα responses directly in the pulmonary granulomas to reduce tissue damage. The bipolar nature of TNFα should be considered as knowledge of this critical molecule continues to grow.