Cytokines are proteins that regulate immune and inflammatory reactions as well as haematopoiesis. This group of molecules is very heterogeneous including, for example, several interleukins (IL), tumour necrosis factors (TNF) and colony-stimulating factors (CSF). The cytokines participating in the regulation of the inflammatory response are IL-1, IL-1 receptor antagonist (IL-1RA), IL-6, IL-10 and TNF. Functionally they can be divided into proinflammatory (IL-1, IL-6, TNF) and anti-inflammatory (IL-1RA, IL-10) molecules. There is evidence that the inflammatory response must be finely tuned: too strong a response causes the various adverse effects associated with infectious and autoimmune diseases, while a weak inflammatory response attenuates the subsequent immune response. It has now been demonstrated that several of the cytokine genes are polymorphic. In this review we describe the polymorphisms of the two inflammatory cytokines, IL-1 and IL-10, and their significance in various diseases of autoimmune or inflammatory nature.

There are indications that the cytokine interleukin (IL)-10 has a regulatory role in Epstein-Barr virus (EBV)-induced infections. Because the human IL-10 gene demonstrates polymorphism resulting in interindividual differences in cytokine production, the frequencies of the alleles defined by the base exchange polymorphism at the position -1082 (allele 1=G, allele 2=A) were analyzed in EBV-seronegative adults, seropositive adults, and in patients hospitalized because of a severe EBV infection. The frequencies of allele 1 were 0.80, 0.46, and 0.29, respectively. Because this allele is associated with a high IL-10-producing capability, these data suggest that high IL-10 levels protect against EBV infection and, conversely, that low IL-10-producing capability makes individuals more susceptible to a severe EBV infection.

Objective To determine whether the haplotypes formed on the basis of single‐base–exchange polymorphisms at positions −1082, −819, or −592 of the interleukin‐10 (IL‐10) gene predispose subjects to primary Sjögren's syndrome (SS). Methods The frequency of IL‐10 polymorphisms was analyzed in 62 patients with primary SS and in 400 healthy subjects. These data were assessed for correlations with the concentration of IL‐10 in the plasma. Results The frequency of the IL‐10 GCC haplotype (G at position −1082, C at position −819, and C at position −592 of the IL‐10 gene) was increased (P < 0.05, odds ratio [OR] 1.90, 95% confidence interval [95% CI] 0.955–3.62) and the frequency of the ACC haplotype decreased (P < 0.05, OR 0.443, 95% CI 0.257–0.764) in primary SS patients compared with healthy controls. Moreover, the frequency of the ATA haplotype was similar in primary SS patients and healthy controls, but the incidence of the GCC/ATA genotype was elevated in the primary SS patients (P < 0.05, OR 2.19, 95% CI 1.19–4.03). The concentration of plasma IL‐10 was significantly higher in patients carrying the GCC haplotype than in non‐carriers of GCC. Conclusion These results suggest that the presence of the GCC haplotype or the GCC/ATA genotype and the absence of the ACC haplotype of the IL‐10 gene are associated with an increased susceptibility to primary SS. This effect is probably mediated by the increased capability to produce IL‐10 among carriers of the GCC haplotype.

The molecular background of the defects in the immune reactivity of human neonates has not been fully elucidated. As the NF-kappa B transcription factor has a central role in the control of transcription of several genes involved in immune and inflammatory responses, the authors have analysed the activation of NF-kappa B in human umbilical cord T lymphocytes. The activity was tested by quantitating the nuclear proteins binding to an oligonucleotide containing the consensus kappa B binding sequence (electrophoretic mobility shift assay). The data obtained demonstrate that phorbol dibutyrate/calcium ionophore A23187 (PDBu/iono) combination induced a clearly higher nuclear translocation of NF-kappa B in neonatal than adult T cells. This higher NF-kappa B activity was restricted to the CD4+ T-cell subset. Analysis of the nuclear extracts with antibodies directed against the major components of NF-kappa B the p50 and RelA (p65) proteins, indicated that the composition of NF-kappa B was similar in neonatal and adult cells. These results suggest that neonatal T cells are exposed to oxidative stress-inducing signals during delivery and/or are inherently more sensitive to NF-kappa B activating signals than adult T cells.

Cyclic AMP (cAMP)-dependent protein kinase A (PKA) is known to have both negative and positive effects on the activation mechanisms of T lymphocytes. The authors have analysed the effect of increased cAMP on the activation of NF-kappa B transcription factor. This factor controls the expression of several genes (e.g. IL-2 and IL-2 receptor) involved in the activation and proliferation of T cells. The authors found that elevation of intracellular cAMP in Jurkat T leukaemia cells activated with phorbol ester (PDBu)/calcium ionophore (A23187) increased the DNA-binding of NF-kappa B as detected by the electrophoretic mobility shift assay (EMSA). Analysis of the subunit composition of the DNA-binding complex indicated that the amount of c-Rel was enhanced while RelA was decreased. Analysis of the effect of elevated cAMP on the degradation of I kappa B-alpha and I kappa B-beta did not reveal an essential change in degradation kinetics of these inhibitor proteins. The elevation of cAMP did not increase the synthesis of c-Rel, but it enhanced the nuclear localization of this protein. Transfection of Jurkat cells with a plasmid kB/TK10-CAT indicated that the increased DNA-binding of c-Rel containing complexes seen in EMSA was also functional. These data imply that the strong and long-lasting c-Rel nuclear localization and DNA-binding induced by protein kinase A is not due to increased c-Rel synthesis or enhanced degradation of the I kappa B inhibitors. Therefore, a direct phosphorylation of the c-Rel protein is the most plausible explanation for these observations. Taken together, these results suggest that cAMP is able to regulate the expression of NF-kappa B-dependent genes in T cells by modifying the composition and subunit activity of NF-kappa B.