Lymphotoxin α3 Induces Chemokines and Adhesion Molecules: Insight into the Role of LTα in Inflammation and Lymphoid Organ Development

Abstract

Abstract Lymphotoxin (LT) plays an important role in inflammation and lymphoid organ development, though the mechanisms by which it promotes these processes are poorly understood. Toward this end, the biologic activities of a recently generated recombinant murine (m) LTα preparation were evaluated. This cytokine preparation was effective at inducing cytotoxicity of WEHI target cells with 50% maximal killing observed with 1.2 ng/ml. mLTα also induced the expression of inflammatory mediators in the murine endothelial cell line bEnd.3. rmLTα induced expression of the adhesion molecules VCAM, ICAM, E-selectin, and the mucosal addressin cellular adhesion molecule, MAdCAM-1. When mLTα, human (h) LTα, and mTNF-α were compared, mLTα was the most potent inducer of MAdCAM-1. None of these cytokines induced the peripheral node addressin, PNAd. mLTα also induced expression of the chemokines RANTES, IFN-inducible protein 10 (IP-10), and monocyte chemotactic protein 1 (MCP-1). mRNA levels peaked 4 h following treatment with mLTα and declined through the 24-h treatment period. LTα also induced chemokine protein within 8 h of treatment, which increased through the 24-h treatment period. These data demonstrate that the proinflammatory effects of LTα3 may be mediated in part through the induction of adhesion molecule and chemokine expression. Further, LTα3 may promote development of lymphoid tissue through induction of chemokines and the mucosal addressin MAdCAM-1. These data confirm previous observations in transgenic and knockout mice that LTα3 in the absence of LTβ carries out unique biologic activities.