LT-BetaR Pathway
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LT-BetaR Pathway
Much of the efficiency of the immune system is attributed to the high degree of spatial and temporal organization in the secondary lymphoid organs. Signaling through the LT-BetaR (Lymphotoxin-Beta Receptor) pathway is a crucial element in the maintenance of this organised microenvironment (Ref.1). LT-BetaR, a member of the TNFR (Tumor Necrosis Factor Receptor) superfamily, plays important roles in embryonic development and organization of secondary lymphoid tissues and maintenance of their architecture in adults (Ref. 2). LT-BetaR is expressed on most cell types including cells of fibroblast, epithelial, and myeloid lineages but not on T or B lymphocytes. It can bind to specific ligands, such as: the membrane form of lymphotoxin heterotrimmer, LT-Alpha1Beta2 (Lymphotoxin-Alpha1Beta2); and homotrimmer LIGHT (name derived from: homologous to Lymphotoxins, Inducible expression, competes with HSV Glycoprotein-D for HVEM, a receptor expressed on T-lymphocytes), a recently identified member of TNF superfamily; and the lymphotoxin LT-Beta (Ref.3). Expression of LT-Alpha1Beta2 is restricted to activated hematopoietic cells, whereas LIGHT is expressed both by the hematopoietic and non-hematopoietic cells. LT-BetaR activates multiple signaling pathways including transcriptional factor NF-KappaB (Nuclear Factor-KappaB), and cell death (Ref.4).

The LT-Alpha1Beta2-LT-BetaR system is required for the formation of lymphoid tissue (lymph nodes and Peyer’s patches) as well as the segregation of T- and B-lymphocytes into distinct compartments in the spleen and the formation of germinal centers, which is accomplished by the expression of adhesion molecules and Chemokines (Ref.5). LT-BetaR binds to TRAFs (TRAF2, -3, -4, and -5,) [TNF Receptor-Associated Factors], and activates NF-KappaB (Nuclear Factor-KappaB) (Ref.2). After triggering of LT-BetaR by LT-Alpha1Beta2, two NF-KappaB pathways are activated (Ref.4). Both the pathways are dependent on the activation of NIK (NF-KappaB-Inducing Kinase). NIK in turn activates IKK-Alpha (Inhibitor of KappaB Kinase-Alpha), which triggers the degradation of the p52 precursor, p100, to yield the mature p52, which heterodimmerizes with RelB. The other NF-KappaB-activating pathway that involves the formation of p50 -RelA heterodimmers, involving the Alpha, Beta and Gamma subunits of the IKK complex, can be turned on after LT-BetaR triggering either by LT-Alpha1Beta2 or LT-Beta (Ref.6).

Nuclear translocation and DNA binding of p50-RelA heterodimmers is accomplished through IKappaB-Alpha phosphorylation and ubiquitin-dependent degradation. In addition, RelA/p65 also induces p100 mRNA (messenger RNA) production, which is required for further p52 production, which, in turn can heterodimmerize with RelB. LT-BetaR signaling triggers the degradation of p100 in a NIK- and IKK-Alpha-dependent manner. As a consequence, IKappaB-Delta is degraded, p52-RelB heterodimmers accumulate in the nucleus and regulate genes that are crucial for the normal development of lymphoid organs through the production of lymphoid chemokines: CCL19 (Chemokine-CC Motif-Ligand-19), CCL21 (Chemokine-CC Motif-Ligand-21), CXCL12 (Chemokine-CXC Motif Ligand-12) and CXCL13; whereas the upregulation of VCAM1 (Vascular-Cell Adhesion Molecule-1) and CXCL1 requires the activation of p50 -RelA heterodimmers (Ref.5). It has been proposed that chemokines are essential for stromal and hematopoietic cells to come together, and LT-BetaR signalling induces the expression of various chemokines that contribute to the essential accumulation of cells (Ref.7). In addition, it has recently been found that the serine/threonine protein kinase Akt, also facilitates the phosphorylation of p65 on Ser529 and Ser536. In response to the activation of PI3K (Phosphatidyl Inositol-3 Kinase) by the LIGHT-actived LT-BetaR, Akt is recruited by PIP3 (phosphatidylinositol- 3,4,5-trisphosphate) and is phosphorylated by PDK-1 (Phosphoinositidedependent Kinase-1) on Thr308 in the kinase domain. Actvated Akt, in turn phosphorylates both p65, and the IKKs (IKK-Alpha, IKK-Beta and IKK-Gamma). Both the events contribute to the activation of NF-KappaB, and the transcription chemokine genes is greatly magnified (Ref.6).

LIGHT protein causes cell death by apoptosis of various tumor cells expressing LT-BetaR. Upon the binding of LIGHT to LT-BetaR, TRAF2 is first recruited to the receptor followed by TRAF3 and cIAP1 (Cellular Inhibitor of Apoptosis-1), during which the BIR1 domain of cIAP1 is cleaved (Ref.8). cIAP1 on the receptor may inhibit activity of Caspases by direct interaction with Caspases. The initial LIGHT-LT-BetaR complex also triggers the mitochondria-mediated apoptosis pathway through the activation of TRAF2 and probably, also through the activation of TRAF3, which induces the release of SMAC (Second Mitochondria-Derived Activator of Caspase) from mitochondria. The cytosolic SMAC is then recruited to the receptor via its interaction with the BIR3 domain of cIAP1. The N-terminus of SMAC antagonizes the function of cIAP1 while the C-terminus works in concert with N-terminus to promote LT-BetaR-induced apoptosis (Ref.9). LIGHT induces growth arrest in cells, inhibits growth of some tumors, and it may serve a costimulatory role in lymphocyte activation, although LIGHT contributes to the formation of mesenteric lymph nodes in some cases (Ref.3).

Inflammation-associated lymphoid organogenesis has been found in some autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and spontaneous autoimmune diabetes (Ref.8). Biological immunosuppressive strategies that are available at present mainly involve the inhibition of pro-inflammatory mediators, such as TNF or Chemokines. The case of LT-BetaR signaling inhibition is unique, as alterations in several lymphoid microenvironments are expected. In future, interruption of these positive-feedback loops by blockade of receptor-mediated signaling might prove to be a successful means of interfering with the formation of inflammatory lesions. The use of LT-BetaR-Ig (LT-BetaR Immunoglobulin) fusion protein is promising, not only because of its ability to modulate microenvironments, but also because it is a dual pathway inhibitor that affects both LIGHT and LT-Alpha1Beta2-induced events (Ref.10).