Roles of soluble and membrane TNF and related ligands in mycobacterial infections: effects of selective and non-selective TNF inhibitors during infection

TNF plays an essential and non-redundant role in host defense mechanisms against Mycobacterium tuberculosis (Mtb) infection. TNF contributes to the development of granulomas, microstructures encasing pathogens and concentrating interactions between phagocytes and lymphocytes, and promotes bactericidal pathways to limit and destroy the invading intracellular pathogen. Production of TNF is associated with the development of human inflammatory diseases, and its inhibition, although an effective therapy, increases the risk of infections including either new or reactivation of tuberculosis infection. Studies on the role of membrane TNF in the absence of secreted TNF using genetic mouse models have shown that membrane TNF protects from M. bovis BCG and acute M. tuberculosis infections but does not induce inflammation in mouse. Pharmacological approaches of selective and non-selective soluble TNF inhibition show that a selective inhibitor of soluble TNF does not suppress host immunity to M. tuberculosis and M. bovis BCG infections, yet protects mice from arthritis and liver inflammatory diseases. This suggests that neutralization of soluble TNF may be effective to inhibit inflammatory diseases and also reduce the infection risks associated with current anti-TNF therapies.