Utilization of the porcine system to study lymphotoxin-beta regulation in intestinal lymphoid tissue.

Lymphotoxin-beta (LT-beta) has been suggested to be a regulator of secondary lymphoid structure development. In the present study, we isolated porcine LT-beta (poLT-beta) from adult swine spleens. The open reading frame encoded a predicted 246-amino acid polypeptide exhibiting higher similarity to the human than the mouse LT-beta protein. Expression of LT-beta mRNA in various swine tissues was analyzed by real-time PCR, and it was found to be higher in the ileal Peyer's patches (Pps) of adults than in newborns. In addition, ligand stimulation of toll-like receptors 2, 4, and 9, which are activated by bacterial components, increased LT-beta expression only in neonatal ileal Pps. These results suggest that colonization by commensal bacteria may affect the maturation of neonatal ileal Pps by the induction of LT-beta via toll-like receptors. LT-beta may therefore be useful for studying the development of the intestinal immune system at parturition in both swine and humans.

Genomic organization and phylogenetic utility of deer mouse (Peromyscus maniculatus) lymphotoxin-alpha and lymphotoxin-beta.

BACKGROUND: Deer mice (Peromyscus maniculatus) are among the most common mammals in North America and are important reservoirs of several human pathogens, including Sin Nombre hantavirus (SNV). SNV can establish a life-long apathogenic infection in deer mice, which can shed virus in excrement for transmission to humans. Patients that die from hantavirus cardiopulmonary syndrome (HCPS) have been found to express several proinflammatory cytokines, including lymphotoxin (LT), in the lungs. It is thought that these cytokines contribute to the pathogenesis of HCPS. LT is not expressed by virus-specific CD4+ T cells from infected deer mice, suggesting a limited role for this pathway in reservoir responses to hantaviruses. RESULTS: We have cloned the genes encoding deer mouse LTalpha and LTbeta and have found them to be highly similar to orthologous rodent sequences but with some differences in promoters elements. The phylogenetic analyses performed on the LTalpha, LTbeta, and combined data sets yielded a strongly-supported sister-group relationship between the two murines (the house mouse and the rat). The deer mouse, a sigmodontine, appeared as the sister group to the murine clade in all of the analyses. High bootstrap values characterized the grouping of murids. CONCLUSION: No conspicuous differences compared to other species are present in the predicted amino acid sequences of LTalpha or LTbeta; however, some promoter differences were noted in LTbeta. Although more extensive taxonomic sampling is required to confirm the results of our analyses, the preliminary findings indicate that both genes (analyzed both separately and in combination) hold potential for resolving relationships among rodents and other mammals at the subfamily level.

Lymphotoxin α induces apoptosis, necroptosis and inflammatory signals with the same potency as tumour necrosis factor.

Both of the TNF superfamily ligands, TNF and LTα, can bind and signal through TNFR1 and TNFR2, yet mice mutant for each have different phenotypes. Part of this difference is because LTα but not TNF can activate Herpes Virus Entry Mediator and also heterotrimerise with LTß to activate LTßR, which is consistent with the similar phenotypes of the LTα and LTßR deficient mice. However, it has also been reported that the LTα3 homotrimer signals differently than TNF through TNFR1, and has unique roles in initiation and exacerbation of some inflammatory diseases. Our modeling of the TNF/TNFR1 interface compared to the LTα3/TNFR1 structure revealed some differences that could affect signalling by the two ligands. To determine whether there were any functional differences in the ability of TNF and LTα3 to induce TNFR1-dependent apoptosis or necroptosis, and if there were different requirements for cIAPs and Sharpin to transmit the TNFR1 signal, we compared the ability of cells to respond to TNF and LTα3. Contrary to our hypothesis, we were unable to discover differences in signalling by TNFR1 in response to TNF and LTα3. Our results imply that the reasons for the conservation of LTα are most likely due either to differential regulation, the ability to signal through Herpes Virus Entry Mediator or the ability of LTα to form heterotrimers with LTß.

Biology and signal transduction pathways of the Lymphotoxin-αß/LTßR system.

This review focuses on the biological functions and signalling pathways activated by Lymphotoxin α (LTα)/Lymphotoxin ß (LTß) and their receptor LTßR. Genetic mouse models shed light on crucial roles for LT/LTßR to build and to maintain the architecture of lymphoid organs and to ensure an adapted immune response against invading pathogens. However, chronic inflammation, autoimmunity, cell death or cancer development are disorders that occur when the LT/LTßR system is twisted. Biological inhibitors, such as antagonist antibodies or decoy receptors, have been developed and used in clinical trials for diseases associated to the LT/LTßR system. Recent progress in the understanding of cellular trafficking and NF-κB signalling pathways downstream of LTα/LTß may bring new opportunities to develop therapeutics that target the pathological functions of these cytokines.