IL-10 and TNFα Genotypes in SLE

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Abstract

The production of two regulators of the inflammatory response, interleukin 10 (IL-10) and tumor necrosis factor α (TNF α), has been found to be deeply deregulated in SLE patients, suggesting that these cytokines may be involved in the pathogenesis of the disease. Genetic polymorphisms at the promoter regions of IL-10 and TNF α genes have been associated with different constitutive and induced cytokine production. Given that individual steady-state levels of these molecules may deviate an initial immune response towards different forms of lymphocyte activation, functional genetic variants in their promoters could influence the development of SLE. The present review summarizes the information previously reported about the involvement of IL-10 and TNF α genetic variants on SLE appearance, clinical phenotype, and outcome. We show that, in spite of the heterogeneity of the populations studied, the existing knowledge points towards a relevant role of IL-10 and TNF α genotypes in SLE.

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Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones

MW Bond, DF Fiorentino, TR Mosmann (1989)

A cytokine synthesis inhibitory factor (CSIF) is secreted by Th2 clones in response to Con A or antigen stimulation, but is absent in supernatants from Con A-induced Th1 clones. CSIF can inhibit the production of IL-2, IL-3, lymphotoxin (LT)/TNF, IFN-gamma, and granulocyte-macrophage CSF (GM-CSF) by Th1 cells responding to antigen and APC, but Th2 cytokine synthesis is not significantly affected. Transforming growth factor beta (TGF-beta) also inhibits IFN-gamma production, although less effectively than CSIF, whereas IL-2 and IL-4 partially antagonize the activity of CSIF. CSIF inhibition of cytokine synthesis is not complete, since early cytokine synthesis (before 8 h) is not significantly affected, whereas later synthesis is strongly inhibited. In the presence of CSIF, IFN-gamma mRNA levels are reduced slightly at 8, and strongly at 12 h after stimulation. Inhibition of cytokine expression by CSIF is not due to a general reduction in Th1 cell viability, since actin mRNA levels were not reduced, and proliferation of antigen-stimulated cells in response to IL-2, was unaffected. Biochemical characterization, mAbs, and recombinant or purified cytokines showed that CSIF is distinct from IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IFN-gamma, GM-CSF, TGF-beta, TNF, LT, and P40. The potential role of CSIF in crossregulation of Th1 and Th2 responses is discussed.

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Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression

J.E. De Vries, H Spits, C Figdor … (1991)

Interleukin 10 (IL-10) and viral IL-10 (v-IL-10) strongly reduced antigen-specific proliferation of human T cells and CD4+ T cell clones when monocytes were used as antigen-presenting cells. In contrast, IL- 10 and v-IL-10 did not affect the proliferative responses to antigens presented by autologous Epstein-Barr virus-lymphoblastoid cell line (EBV-LCL). Inhibition of antigen-specific T cell responses was associated with downregulation of constitutive, as well as interferon gamma- or IL-4-induced, class II MHC expression on monocytes by IL-10 and v-IL-10, resulting in the reduction in antigen-presenting capacity of these cells. In contrast, IL-10 and v-IL-10 had no effect on class II major histocompatibility complex (MHC) expression on EBV-LCL. The reduced antigen-presenting capacity of monocytes correlated with a decreased capacity to mobilize intracellular Ca2+ in the responder T cell clones. The diminished antigen-presenting capacities of monocytes were not due to inhibitory effects of IL-10 and v-IL-10 on antigen processing, since the proliferative T cell responses to antigenic peptides, which did not require processing, were equally well inhibited. Furthermore, the inhibitory effects of IL-10 and v-IL-10 on antigen-specific proliferative T cell responses could not be neutralized by exogenous IL-2 or IL-4. Although IL-10 and v-IL-10 suppressed IL-1 alpha, IL-1 beta, tumor necrosis factor alpha (TNF- alpha), and IL-6 production by monocytes, it was excluded that these cytokines played a role in antigen-specific T cell proliferation, since normal antigen-specific responses were observed in the presence of neutralizing anti-IL-1, -IL-6, and -TNF-alpha mAbs. Furthermore, addition of saturating concentrations of IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha to the cultures had no effect on the reduced proliferative T cell responses in the presence of IL-10, or v-IL-10. Collectively, our data indicate that IL-10 and v-IL-10 can completely prevent antigen-specific T cell proliferation by inhibition of the antigen-presenting capacity of monocytes through downregulation of class II MHC antigens on monocytes.

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Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation.

A Wilson, J A Symons, T McDowell … (1997)

Tumor necrosis factor alpha (TNF alpha) is a potent immunomodulator and proinflammatory cytokine that has been implicated in the pathogenesis of autoimmune and infectious diseases. For example, plasma levels of TNF alpha are positively correlated with severity and mortality in malaria and leishmaniasis. We have previously described a polymorphism at -308 in the TNF alpha promoter and shown that the rare allele, TNF2, lies on the extended haplotype HLA-A1-B8-DR3-DQ2, which is associated with autoimmunity and high TNF alpha production. Homozygosity for TNF2 carries a sevenfold increased risk of death from cerebral malaria. Here we demonstrate, with reporter genes under the control of the two allelic TNF promoters, that TNF2 is a much stronger transcriptional activator than the common allele (TNF1) in a human B cell line. Footprint analysis using DNase I and B cell nuclear extract showed the generation of a hypersensitive site at -308 and an adjacent area of protection. There was no difference in affinity of the DNA-binding protein(s) between the two alleles. These results show that this polymorphism has direct effects on TNF alpha gene regulation and may be responsible for the association of TNF2 with high TNF alpha phenotype and more severe disease in infections such as malaria and leishmaniasis.

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Author and article information

Journal

Journal ID (nlm-ta): J Biomed Biotechnol

Journal ID (publisher-id): JBB

Title: Journal of Biomedicine and Biotechnology

Publisher: Hindawi Publishing Corporation

ISSN (Print): 1110-7243

ISSN (Electronic): 1110-7251

Publication date (Print): 2010

Publication date (Electronic): 21 June 2010

Volume: 2010

Electronic Location Identifier: 838390

Affiliations

¹Department of Functional Biology, Immunology Area, University of Oviedo, 33006 Oviedo, Asturias, Spain

²Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias (CSIC), 33300 Villaviciosa, Asturias, Spain

³Department of Immunology, Hospital Universitario Central de Asturias, 33006 Oviedo, Asturias, Spain

Author notes

*Ana Suárez: anasua@ 123456uniovi.es

Academic Editor: Timothy B. Niewold

Article

DOI: 10.1155/2010/838390

PMC ID: 2896901

PubMed ID: 20625422

SO-VID: d3f5acdc-390e-4330-81be-818433d3b35f

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 15 January 2010

Date accepted : 20 April 2010

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IL-10 and TNF α Genotypes in SLE

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Most cited references 128

Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones

Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression

Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation.

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