Disease relevance of LTB

• The gene for LT beta was found next to the TNF-LT locus in the major histocompatibility complex (MHC), a region of the MHC with possible linkage to autoimmune disease [1].
• Of the frequently detectable cytokines, IFN-gamma and LT beta were commonly detected in the EBV negative cases [2].
• Escherichia coli producing LTA* and LTB (LT toxoids) could be useful as a vaccine [3].
• Identification of two lymphotoxin beta isoforms expressed in human lymphoid cell lines and non-Hodgkin's lymphomas [4].
• Two isoforms of lymphotoxin beta (LTbeta) were isolated from mRNAs of a panel of human lymphoid cell lines and tumor tissues obtained from patients with non-Hodgkin's lymphoma (NHL) [4].

High impact information on LTB

• These observations raise the possibility that a surface LT alpha-LT beta complex may have a specific role in immune regulation distinct from the functions ascribed to TNF [1].
• A receptor specific for human LT-beta was identified, which suggests that cell surface LT may have functions that are distinct from those of secreted LT-alpha [5].
• Using dominant-negative proteins that inhibit NFAT5 dimerization, we show that NFAT5 regulates expression of the TNFalpha and lymphotoxin-beta genes in osmotically stressed T cells [6].
• LIGHT is a 29 kDa type II transmembrane protein produced by activated T cells that also engages the receptor for the LTalphabeta heterotrimer but does not form complexes with either LTalpha or LTbeta [7].
• In contrast, as shown previously and confirmed in this study, LTbeta-deficient mice show much more conserved T/B cell areas and a reduced but preserved capacity to form germinal centers and FDC networks [8].

Chemical compound and disease context of LTB

• Particular alleles of the tumor necrosis factor gene cluster (TNFA, LTA, LTB) are known to be associated with peculiar clinical forms of sarcoidosis [9].
• The closely related B-subunits of cholera toxin (CTB) and Escherichia coli heat-labile enterotoxin (LTB) both bind strongly to GM1 ganglioside receptors but LTB can also bind to additional glycolipids and glycoproteins [10].
• We now report the structure determination and 2.3-A refinement of the CTB mutant Gly 33-->Arg complexed with the GM1 oligosaccharide, as well as the 2.2-A refinement of a Gly 33-->Asp mutant of the closely related Escherichia coli heat-labile enterotoxin B-pentamer (LTB) [11].

Biological context of LTB

• In investigating the reported upregulation of LT-beta during inflammation, we tested the effects of various proinflammatory and anti-inflammatory cytokines on LT-beta expression [12].
• In addition, the observation of striking similarities between the mRNA accumulation kinetics of LT-alpha and LT-beta during these treatments indicates tight coupling of expression under certain conditions [12].
• Membrane-anchored LTbeta expressed on the cell surface in absence of the LTalpha subunit binds the LTbetaR but is functionally inactive in the cell death assay [13].
• The pattern of LTbeta gene expression was different from that of the other molecules, indicating the existence of distinct mechanisms of gene regulation [14].
• Skipping out of exon 2 causes a reading frame shift and a premature stop codon in the LTbeta mRNA variant [4].

Anatomical context of LTB

• By using a battery of anti-LT-alpha and LT-beta mAbs, it is clear that two LT surface forms exist on the surface of PMA-activated II-23 cells, a human T cell hybridoma [15].
• LT beta expression was seen on astrocytes and oligodendrocytes, and LT beta-R on astrocytes [16].
• In contrast, these mutant LTalpha proteins retain the ability to co-assemble with LTbeta into membrane-anchored LTalpha1beta2 complexes that engage the LTbetaR and trigger the death of HT29 cells [13].
• Thus LT-beta and alpha appear to be sequentially expressed in human B cells [17].
• Although, TNF-beta mRNA was detected in amnion, choriodecidual and placenta, LT-beta was similarly expressed in these tissues, suggesting that TNF-beta may be cell membrane bound [18].

Associations of LTB with chemical compounds

• Biosynthetic labeling studies showed that p33 contained both methionine and cysteine, whereas the p25 contained only methionine [19].
• Regulation of lymphotoxin-beta by tumor necrosis factor, phorbol myristate acetate, and ionomycin in Jurkat T cells [12].
• Although lymphotoxin alpha (LT-alpha) mRNA is induced by both pathways, it is not blocked by CsA, whereas LT-beta mRNA is constitutively expressed in B cells [20].
• Antibodies to rLT precipitated both surface LT and a distinct 33-kDa glycoprotein (p33) [21].
• Cyclosporin A blocks the expression of lymphotoxin alpha, but not lymphotoxin beta, in human peripheral blood mononuclear cells [22].

Physical interactions of LTB

• LT beta is a transmembrane protein that provides the membrane anchor for the attachment to the cell surface of the heteromeric complex of LT alpha and LT beta [23].

Regulatory relationships of LTB

• TNF and phorbol esters induce lymphotoxin-beta expression through distinct pathways involving Ets and NF-kappa B family members [24].
• These findings demonstrate that cell-surface LT-alpha is expressed in association with LT-beta on activated normal B cells and neoplastic B cells representing an activated state [17].
• Further, stable overexpression of a TRAF3 mutant that lacks the RING and zinc finger domains inhibits LTbeta R-mediated cell death [25].
• Lymphotoxin beta (LTalpha1beta2) expressed on the membrane of immune cells triggers CCL20 expression in enterocytes [26].

Other interactions of LTB

• Our data demonstrate an upregulation of LT-beta mRNA by the inflammatory cytokines TNF and LT-alpha [12].
• These results indicate that the TNF receptor-binding regions of the LTalpha subunit are not necessary for engagement of the LTbetaR, but the LTalpha subunit is required for the assembly of LTbeta into a functional heteromeric ligand [13].
• RESULTS: The expression of LT-beta in hepatic oval cell and hepatocellular carcinoma cell lines was further investigated, along with its responsiveness to IL-6 and IL-1beta [27].
• These results implicate TRAF3 as a critical component of the LTbeta R death signaling complex and indicate that at least two independent signaling pathways are initiated by LTbeta R ligation [25].
• Proliferating human medullary thymocytes can exhibit characteristic T helper cell type 1 cytokine responses exemplified by the immediate early expression of interleukin-2, interferon-gamma, tumor necrosis factor-alpha, and lymphotoxin-beta [28].

Analytical, diagnostic and therapeutic context of LTB

• Thus, cosignaling via the LT-beta and TNF-alpha receptors is probably involved in the modulation of HIV-1 replication and the subsequent determination of HIV-1 viral burden in monocytes [29].
• In situ hybridization demonstrates constitutive expression of LT-beta in lymphoid and hematopoietic tissues [30].
• In this study, a polyclonal anti-serum to human LT-beta was used to investigate the distribution of LT-beta by immunohistochemistry in normal and diseased tissues [31].
• Transplantation of lymphoid tissues from LT-beta -/- mice, which have cervical and mesenteric lymph nodes, into LT-alpha -/- mice, which do not, did not alter the incidence of CNS scrapie [32].
• LT-beta is a type II membrane-bound protein that anchors the complex to the surface of activated lymphocytes and, in gene targeting experiments in mice, has been shown to be crucial for normal lymphoid organogenesis [33].

References