Lymphotoxin alpha3 induces chemokines and adhesion molecules: insight into the role of LT alpha in inflammation and lymphoid organ development.
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) LT alpha 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. mLT alpha also induced the expression of inflammatory mediators in the murine endothelial cell line bEnd.3. rmLT alpha induced expression of the adhesion molecules VCAM, ICAM, E-selectin, and the mucosal addressin cellular adhesion molecule, MAdCAM-1. When mLT alpha, human (h) LT alpha, and mTNF-alpha were compared, mLT alpha was the most potent inducer of MAdCAM-1. None of these cytokines induced the peripheral node addressin, PNAd. mLT alpha 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 mLT alpha and declined through the 24-h treatment period. LT alpha 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 LT alpha3 may be mediated in part through the induction of adhesion molecule and chemokine expression. Further, LT alpha3 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 LT alpha3 in the absence of LT beta carries out unique biologic activities.
Cuff
C A
CA
Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06520, USA.
Schwartz
J
J
Bergman
C M
CM
Russell
K S
KS
Bender
J R
JR
Ruddle
N H
NH
D000818:Animals; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics; D054357:Chemokine CXCL10; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D019040:E-Selectin / Q000096:biosynthesis / Q000235:genetics; D005314:Embryonic and Fetal Development; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis / Q000235:genetics; D007249:Inflammation / Q000503:physiopathology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D008221:Lymphoid Tissue / Q000196:embryology*; D008233:Lymphotoxin-alpha / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D015846:Monokines / Q000096:biosynthesis / Q000235:genetics; D009088:Mucoproteins / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013045:Species Specificity; D013268:Stimulation, Chemical; D014407:Tumor Cells, Cultured; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics
D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; D019040:E-Selectin; D007136:Immunoglobulins; D008233:Lymphotoxin-alpha; C504265:MADCAM1 protein, human; D019402:Macrophage Inflammatory Proteins; C489082:Madcam1 protein, mouse; D015846:Monokines; D009088:Mucoproteins; D011993:Recombinant Fusion Proteins; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1