Effects of three anti-TNF-alpha drugs: etanercept, infliximab and pirfenidone on release of TNF-alpha in medium and TNF-alpha associated with the cell in vitro.
Tumor necrosis factor-alpha (TNF-alpha) 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-alpha, either with neutralizing anti-TNF-alpha binding proteins such as etanercept or via drugs that inhibit de novo TNF-alpha synthesis like pirfenidone. In the present study, we examined the effects of both classes of drugs on secreted and cell-associated TNF-alpha produced by THP-1 cells. All of the tested drugs significantly reduced secreted levels of bioactive TNF-alpha following stimulation with LPS as measured by bioassay. However, etanercept-treated cells had approximately six-fold higher levels of cell-associated TNF-alpha compared with that of the LPS-alone treatment group. Surprisingly, LPS+infliximab treated cells did not increase cell-associated TNF-alpha relative to the LPS-alone treatment. Pirfenidone significantly reduced both secreted and cell-associated TNF-alpha levels. These drug-related differences in cell-associated TNF-alpha may have broad implications in the future for the therapeutic uses of anti-TNF-alpha drugs in the management of TNF-alpha diseases.
Grattendick
K J
KJ
Solanan, Inc., Dallas, TX 75229, USA.
Nakashima
J M
JM
Feng
L
L
Giri
S N
SN
Margolin
S B
SB
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media; D004797:Enzyme-Linked Immunosorbent Assay; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D007150:Immunohistochemistry; D000069285:Infliximab; D008070:Lipopolysaccharides / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology*; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D003470:Culture Media; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D011728:Pyridones; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; C093844:pirfenidone; D000068800:Etanercept