Loss of Lymphotoxin-α but Not Tumor Necrosis Factor-α Reduces Atherosclerosis in Mice

Abstract

Inflammatory processes are involved with all phases of atherosclerotic lesion growth. Tumor necrosis factor-␣ (TNF␣) is an inflammatory cytokine that is thought to contribute to lesion development. Lymphotoxin-␣ (LT␣) is also a proinflammatory cytokine with homology to TNF␣. However, its presence or function in lesion development has not been investigated. To study the role of these molecules in atherosclerosis, the expression of these cytokines in atherosclerotic lesions was examined. The presence of both cytokines was observed within aortic sinus fatty streak lesions. To determine the function of these molecules in regulating lesion growth, mice deficient for TNF␣ or LT␣ were examined for induction of atherosclerosis. Surprisingly, loss of TNF␣ did not alter lesion development compared with wild-type mice. This brings doubt to the generally held concept that TNF␣ is a "proatherogenic cytokine." However, LT␣ deficiency resulted in a 62% reduction in lesion size. This demonstrates an unexpected role for LT␣ in promoting lesion growth. The presence of LT␣ was observed in aortic sinus lesions suggesting a direct role of LT␣ in modulating lesion growth. To determine which receptor mediated these responses, diet-induced atherosclerosis in mice deficient for each of the TNF receptors, termed p55 and p75, was examined. Results demonstrated that loss of p55 resulted in increased lesion development, but loss of p75 did not alter lesion size. The disparity in results between ligand-and receptor-deficient mice suggests there are undefined members of the TNF ligand and receptor signaling pathway involved with regulating atherogenesis.Inflammatory processes are an integral component to atherosclerotic lesion development. Cytokine-mediated proinflammatory responses such as endothelial cell activation and leukocyte recruitment are thought to positively contribute to the atherogenic process. One of the best-studied proinflammatory cytokines is tumor necrosis factor-␣ (TNF␣) 1 that is expressed in both human and rodent atherosclerotic plaques (1-5). However, the physiological role of TNF ligand and receptor family members in the atherogenic process remains unclear.TNF␣ and lymphotoxin-␣ (LT␣) are two predominant members of the TNF ligand family. Their structural genes are located on human chromosome 6 within the major histocompatibility complex (6). TNF␣ and LT␣ proteins are structurally similar and display 50% amino acid homology (7). TNF␣ is first synthesized as a type II transmembrane protein and is subsequently cleaved to form circulating homotrimeric TNF␣ (8). TNF␣ is synthesized primarily by activated macrophages (9), although under appropriate stimulation other cells can express this cytokine (10 -12). TNF␣ influences the function of macrophages, smooth muscle cells, and endothelial cells (13), which are major cell types observed in plaques. LT␣ is synthesized primarily by activated T and B lymphocytes (6, 7) and is also found in the circulation as a homotrimer. Unlike TNF␣, membrane-bound homotrimeric LT␣ has not been o...

Up-Regulation of Cell Adhesion Molecule Genes in Human Endothelial Cells Stimulated by Lymphotoxin Alpha: DNA Microarray Analysis

“…Briefly, loss of the TNF gene did not alter atherosclerotic lesion development compared with wild-type mice, but LTA deficiency resulted in a 62% reduction in lesion size 29) ; however, genes up-regulated by LTA in the present study were almost identical to those induced by TNF 23) . These observations are possibly explained by the activation of TNFR and by TNF and LTA.…”

Characterization of Resident B Cells of Vascular Walls in Human Atherosclerotic Patients

“…Elevated serum levels of these cytokines are generally found in patients having a poor prognosis or more severe arterial lesions (55,56). Animal models designed to decipher the role of IL-6, TNF-a, and GM-CSF in atherosclerosis have not yet been fully conclusive because experimental settings (feeding diet, location of the lesions, and sex of the animals) largely determine the outcome of lesion evolution (57)(58)(59)(60)(61)(62)(63)(64). In this study we show that IL-6, TNF-a, and GM-CSF production is inconstant but characteristic of resident B cells, whereas the lack of expression of the other tested cytokines is a permanent feature.…”

The unexpected role of lymphotoxin β receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development

“…This includes an important role of LT signaling in the acceptance of donor stem cells, controlling cuprizone-induced demyelination, the progression of experimental autoimmune encephalomyelitis and the control of lipid metabolism or liver regeneration Lo et al, 2007;Plant et al, 2007;Markey et al, 2009;Ruddell et al, 2009;Tumanov et al, 2009). Studies with different mouse models revealed a role of LTbR signaling in atherosclerosis development (Schreyer et al, 2002;Grabner et al, 2009) and an involvement of LTbR signaling was discovered in the pathogenesis of RA (Fava et al, 2003). Blocking LTbR signaling using a LTbR-Ig fusion protein could prevent the onset of collagen-induced arthritis or reduce its severity, depending on the time point of LTbR-Ig treatment (Fava et al, 2003).…”