The Yin-Yang of TNFalpha in the guinea pig model of tuberculosis.

Tumour necrosis factor alpha (TNF-alpha) 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 TNFalpha data acquired from the 'gold standard' guinea pig animal model of tuberculosis. While production of TNFalpha is widely accepted as beneficial to the host response, we have found that this hypothesis is just one side of the story. TNFalpha can up-regulate and down-regulate some key pro-inflammatory cytokines (IFNgamma, IL-12p40) and differentially modulate macrophage activation and intracellular bacterial growth. Neutralization of TNFalpha in vivo allows an antiinflammatory TGFbeta-mediated response to develop. Furthermore, BCG vaccination modulates TNFalpha responses directly in the pulmonary granulomas to reduce tissue damage. The bipolar nature of TNFalpha should be considered as knowledge of this critical molecule continues to grow.