Inhibition of tumor necrosis factor and lymphotoxin

At the ligand level, an important control mechanism for the production of TNFa is the release of the membrane-bound (26 kDa) precursor controlled by the metalloproteinase TNFa-converting enzyme (TACE). TNFa and lymphotoxin (LTa) (previously-called TNF0) act after binding to membrane-bound p55 (or p60, or type I) and p75 (or p80 or type II) receptors expressed by numerous types of cells. Both exist in soluble forms, detected in vitro and in vivo, and are released from the cell surface after proteolytic cleavage, possibly mediated by an unidentified metalloproteinase. Of the two receptors p7.5 is shed more frequently. Among the stimuli that enhance TNF receptors shedding is TNFa itself. Since soluble receptors have a longer half-life than TNFa, it is easier to detect in body fluids the levels of soluble TNF receptors which reflect previous or ongoing TNF responses. The affinity of soluble receptors for TNFa and LTa nearly equals that of membrane receptors. Thus, they may act as buffers, although they may also act as carriers and prolong TNFa bioavailability. Soluble TNF receptors circulate in nanogram amounts in human blood, but are increased in various inflammatory diseases and control the bioactivity of TNFa. Chimeric protein molecules consisting of an Fc portion of the human IgGl coupled to p55 or p75 TNF soluble receptors are at present being evaluated in clinical trials to treat chronic inflammatory autoimmune disorders such as rheumatoid arthritis and severe acute inflammatory or infectious diseases.

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Arthritis Relief and Prevention

Arthritis Relief and Prevention

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