Progress in Basic and Clinical Immunology pp 129-139
Allele specific regulation of cytokine genes: Monoallelic expression of the IL-lA gene
The host immune response strongly controls the susceptibility and outcome of inflammatory and infectious diseases in humans. Cytokines play an important role in this response as crucial intercellular signaling molecules that are responsible for multidirectional communication among immune and inflammatory cells engaged in host defense. They exert their effects by binding to high-affinity receptors expressed on target cells thereby inducing biochemical signals within these cells which profoundly change their behaviour. It has become clear that cytokines not only play important roles in tissue homeostasis but also in the pathogenesis of many immune related disorders. A large body of evidence indicated that the cytokine profile, examplified by the balance between inflammatory and anti-inflammatory activities, is a determining factor in the progress of the immune response and the maintenance of tissue homeostasis and might provide an explanation for interindividual differences in the host immune response. A critical question to be answered is which molecular mechanism underlies the imbalance of pro-and anti-inflammatory activity in immune related disease. Clinically useful information should come from understanding the molecular regulatory steps underlying the imbalance in the cytokine profile that would allow the identification of people who display an imbalance in their cytokine profile enabling clinicians to predict outcomes and to tailor treatment.
Unable to display preview. Download preview PDF.
- 2.Jacob, C.O., Fronek, Z., Lewis, G.D., Koo, M., Hansen, J.A., McDevitt, H.O., 1990, Heritable major histocompatibility complex class II-associated differences in production of TNFa: relevance to genetic predisposition to systemic lupus erythematosus. Proc Natl Acad Sci USA 87: 1233–1237.PubMedCrossRefGoogle Scholar
- 3.Pociot, F., Briant, L., Jongeneel, C.V., Molvig, J., Worsaae, H., Abbal, M., Thomson, M., Nerup, J., Cambon-Thomsen, A., 1993, Association of TNF and class II MHC alleles with the secretion of TNF-alpha and TNF-beta by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus. Eur J Immunol 23: 224–232PubMedCrossRefGoogle Scholar
- 6.Gazznelli, R.T., Wysocka, M., Hieny, S. et al., 1996, In the absence of endogenous IL-10, mice acutely infected withToxoplasma gondiisuccumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFNy, and TNFa. J Immunol 157: 798–805Google Scholar
- 13.van Krugten, M.V., Huizinga, T.W.J., Kaijzel, E.L., Drossears-Bakker, K.W., van de Linde, P., Zanelli, E., Hazes, J.M.W., Zwinderman, A.H., Breedveld, F.C., Verweij, C.L.,1999, Association of the TNF +489 polymorphism with susceptibility and radiographic damage in rheumatoid arthritis patients. Genes Immunity 1: 1–6CrossRefGoogle Scholar
- 14.Kaijzel, E.L., van Krugten, M.V., Brinkman, B.M.N., Huizinga, T.W.J., Breedveld, F.C., and Verweij, C.L. 1998, Functional analysis of a human tumor necrosis factor alpha promoter polymorphism related to joint damage in rheumatoid arthritis. Molec. Med. 4: 724–733Google Scholar
- 15.Brinkman, B.M.N., Zuijdgeest, D., Kaijzel, E.L., Breedveld, F.C., Verweij, C.L., 1996, Relevance of the tumor necrosis factor alpha (TNF alpha) - 308 promoter polymorphism in TNF alpha gene regulation. J Inflamm 46: 32–41.Google Scholar
- 16.Stuber, F., Udalova, I.A., Book, M., Drutskaya, L.N., Kuprash, D.V., Turetskaya, R.L., Schade, F.U., Nedospasov, S.A.,1996, -308 tumor necrosis factor (TNF) polymorphism is not associated with survival in severe sepsis and is unrelated to lipopolysaccharide inducibility of the human TNF promoter. J Inflamm 46: 42–50.Google Scholar
- 21.Brinkman, B.M.N., Huizinga, T.W.J., Breedveld, F.C., and Verweij, C.L. 1996, Allele-specific quantification of TNFA transcripts in rheumatoid arthritis. Hum. Genet. 97: 813818Google Scholar
- 22.Kaijzel, E.L., Bayley, J.P., van Krugten, M.V., Smith, L., van de Linde P., Bakker, A.L., Huizinga, T.W.J., and Verweij, C.L. 2001, Allele specific quantification of tumor necrosis factor (TNF) transcription and the role of promoter polymorphisms in rheumatoid arthritis and healthy individuals. Genes Immun. in pressGoogle Scholar
- 24.Bix, M., and Locksley, R., 1998, Science 281: 1352–1354Google Scholar