Differential Activities of Secreted Lymphotoxin-α3 and Membrane Lymphotoxin-α1β2 in Lymphotoxin-Induced Inflammation: Critical Role of TNF Receptor 1 Signaling

Abstract

Lymphotoxin (LT, LTα, TNFβ) is a member of the immediate TNF family that also includes TNF-α and lymphotoxin-β (LTβ). LT is produced by activated lymphocytes and functions as either a secreted homotrimer or a membrane-associated heterotrimer that includes the transmembrane protein LTβ. Secreted LTα3 can bind to two cell surface receptors, TNFR1 and TNFR2, while the membrane-bound heterotrimer LTα1β2 has been shown to interact with a distinct receptor, LTβR. LTα induces inflammation at the sites of expression of a rat insulin promoter-driven lymphotoxin (RIPLT) transgene in the pancreas and kidney. To determine the role of the various ligands and their receptors in LT-induced inflammation, mice deficient in either TNFR1, TNFR2, or LTβ were crossed to RIPLT-transgenic mice. Our results indicate that LTα-induced inflammation is dependent on the interaction of LTα3 with TNFR1, and there is no obvious role for TNFR2, since in its absence, LTα-induced inflammation is quantitatively and qualitatively similar to that seen in the wild type. However, the absence of LTβ results in accentuated infiltration of the kidney with an increase in the proportion of memory cells in the infiltrate. These data show a crucial role for the secreted LTα3 signaling via TNFR1 in LTα-induced inflammation, and a separate and distinct role for the membrane LTα1β2 form in this inflammatory process.