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Effects of three anti-TNF-α drugs : Etanercept , infliximab and pirfenidone on release of TNF-α in medium and TNF-α associated with the cell in vitro

Tumor necrosis factor-alpha (TNF-α) is a vital component of the inflammatory process and its aberrant over-expression has been linked to numerous disease states. New treatment strategies have sought to reduce circulating TNF-α, either with neutralizing anti-TNF-α binding proteins such as etanercept or via drugs that inhibit de novo TNF-α synthesis like pirfenidone. In the present study, we examined the effects of both classes of drugs on secreted and cell-associated TNF-α produced by THP-1 cells. All of the tested drugs significantly reduced secreted levels of bioactive TNF-α following stimulation with LPS as measured by bioassay. However, etanercepttreated cells had approximately six-fold higher levels of cell-associated TNF-α compared with that of the LPS-alone treatment group. Surprisingly, LPS+ infliximab treated cells did not increase cell-associated TNF-α relative to the LPS-alone treatment. Pirfenidone significantly reduced both secreted and cell-associated TNF-α levels. These drug-related differences in cellassociated TNF-αmay have broad implications in the future for the therapeutic uses of anti-TNFα drugs in the management of TNF-α diseases. © 2008 Elsevier B.V. All rights reserved.