Binding activities of infliximab and etanercept to transmembrane tumor necrosis factor-α

Abstract

Dear Sir: We read with interest the article entitled “Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease” by van den Brande et al.1Van den Brande J.M.H. Braat H. van den Brink G.R. Versteeg H.H. Bauer C.A. Hoedemaeker I. van Montfrans C. Hommes D.W. Peppelenbosch M.P. van Deventer S.J.H. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease.Gastroenterology. 2003; 124: 1774-1785Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar The 2 types of TNF antagonists, infliximab (chimeric anti-TNF-α antibody), and etanercept (recombinant TNF receptor/immunoglobulin G fusion protein), have been shown to be equally effective against rheumatoid arthritis; however, only infliximab was effective in Crohn’s disease, the other TNF-mediated disease. The authors concluded that infliximab, but not etanercept, binds to the transmembrane TNF-α on lamina propria T cells from patients with Crohn’s disease, and only infliximab-induced apoptosis of activated lymphocytes. In the article, the inability of etanercept on the binding to transmembrane TNF-α was suggested to explain the difference in the biological effects of these 2 types of TNF antagonists in the clinical settings. There are 2 points we would like to discuss. First is on the mechanism of infliximab-induced T cell apoptosis. As they implicated, outside-to-inside (reverse) signal from transmembrane TNF-α is likely the cause of infliximab-induced apoptosis. Our group and others have shown that stimulation of transmembrane TNF-α with polyclonal anti-TNF-α induced several biological effects including calcium mobilization,2Higuchi M. Nagasawa K. Horiuchi T. Oike M. Ito Y. Yasukawa M. Niho Y. Membrane tumor necrosis factor-α (TNF-α) expressed on HTLV-infected T cells mediates a costimulatory signal for B cell activation-characterization of membrane TNF-α.Clin Immunol Immunopathol. 1997; 82: 133-140Crossref PubMed Scopus (62) Google Scholar, 3Watts A.D. Hunt N.H. Wanigasekara Y. Bloomfield G. Wallach D. Roufogalis B.D. Chaudhri G. A casein kinase I motif present in the cytoplasmic domain of members of the tumoir necrosis factor ligand family is implicated in ‘reverse signalling’.EMBO J. 1999; 18: 2119-2126Crossref PubMed Scopus (162) Google Scholar cytokine production,2Higuchi M. Nagasawa K. Horiuchi T. Oike M. Ito Y. Yasukawa M. Niho Y. Membrane tumor necrosis factor-α (TNF-α) expressed on HTLV-infected T cells mediates a costimulatory signal for B cell activation-characterization of membrane TNF-α.Clin Immunol Immunopathol. 1997; 82: 133-140Crossref PubMed Scopus (62) Google Scholar, 4Eissner G. Kirchner S. Lindner H. Kolch W. Janosch P. Grell M. Scheurich P. Andreesen R. Holler E. Reverse signaling through transmembrane TNF confers resistance to lipopolysaccharide in human monocytes and macrophages.J Immunol. 2000; 164: 6193-6198PubMed Google Scholar and E-selectin expression on T cells.5Harashima S. Horiuchi T. Hatta N. Morita C. Higuchi M. Sawabe T. Tsukamoto H. Tahira T. Hayashi K. Fujita S. Niho Y. Outside-to-inside signal through the membrane TNF-α induces E-selection (CD62E) expression on activated human CD4+ T cells.J Immunol. 2001; 166: 130-136PubMed Google Scholar These lines of evidence support the presence of reverse signal through transmembrane TNF-α in infliximab-induced apoptosis as well. Second, we suppose that etanercept binds to transmembrane TNF-α as well as infliximab, which does not agree with the data by van den Brande et al.1Van den Brande J.M.H. Braat H. van den Brink G.R. Versteeg H.H. Bauer C.A. Hoedemaeker I. van Montfrans C. Hommes D.W. Peppelenbosch M.P. van Deventer S.J.H. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease.Gastroenterology. 2003; 124: 1774-1785Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar Binding of etanercept as well as infliximab to uncleavable form of transmembrane TNF-α (amino acids 1–12 of mature TNF deleted) on mouse myeloma K2 cells has already been demonstrated,6Scallon B. Cai A. Solowski N. Rosenberg A. Song X.-Y. Shealy D. Wagner C. Binding and functional comparisons of two types of tumor necrosis factor antagonists.J Pharmacol Exp Ther. 2002; 301: 418-426Crossref PubMed Scopus (593) Google Scholar although more infliximab bound to the transmembrane TNF-α with higher avidity than etanercept. In addition, we here show that etanercept and infliximab bound to wild-type transmembrane TNF-α stably expressed on Jurkat T cells (Figure 1). In our experimental condition, infliximab again bound to the transmembrane TNF-α with higher avidity than etanercept as judged by the mean fluorescence level. Taken together, we suggest that etanercept binds to the transmembrane form of TNF-α, although with less avidity compared to that of infliximab, and thus could not transmit sufficient signals to initiate apoptosis in lamina propria T cells. The action mechanisms of infliximab and etanercept should further be examined. Reply to HoriuchiGastroenterologyVol. 126Issue 3Preview Full-Text PDF