DIFFERENTIAL ACTIVITIES OF SECRETED LYMPHOTOXIN-ALPHA(3) AND MEMBRANELYMPHOTOXIN-ALPHA(1)BETA(2) IN LYMPHOTOXIN-INDUCED INFLAMMATION - CRITICAL ROLE OF TNF RECEPTOR-1 SIGNALING

Lymphotoxin (LT, LT alpha, TNF beta) is a member of the immediate TNF family that also includes TNF-alpha and lymphotoxin-beta (LT beta). LT is produced by activated lymphocytes and functions as either a secret ed homotrimer or a membrane-associated heterotrimer that includes the transmembrane protein LT beta. Secreted LT alpha(3) can bind to two ce ll surface receptors, TNFR1 and TNFR2, while the membrane-bound hetero trimer LT alpha(1) beta(2) has been shown to interact with a distinct receptor, LT beta R. LT alpha induces inflammation at the sites of exp ression of a rat insulin promoter-driven lymphotoxin (RIPLT) transgene in the pancreas and kidney, To determine the role of the various liga nds and their receptors in LT-induced inflammation, mice deficient in either TNFR1, TNFR2, or LT beta were crossed to RIPLT-transgenic mice. Our results indicate that LT alpha-induced inflammation is dependent on the interaction of LT alpha(3) with TNFR1, and there is no obvious role for TNFR2, since in its absence, LT alpha-induced inflammation is quantitatively and qualitatively similar to that seen in the wild typ e. However, the absence of LTP results in accentuated infiltration of the kidney with an increase in the proportion of memory cells in the i nfiltrate. These data show a crucial role for the secreted LT alpha(3) signaling via TNFR1 in LT alpha-induced inflammation, and a separate and distinct role for the membrane LT alpha(1) beta(2) form in this in flammatory process.