Mikko Hurme

IL‐1 receptor antagonist (IL‐1Ra) plasma levels are co‐ordinately regulated by both IL‐1Ra and IL‐1β genes

The genes in the IL‐1 complex code for three proteins, IL‐1α, IL‐1β and the IL‐1 receptor antagonist (IL‐1Ra). The severity of a given infection is influenced by the balance between the levels of IL‐1β, the major extracellular agonist, and that of IL‐1Ra. In healthy individuals, IL‐1Ra is readily detectable in plasma but IL‐1β levels are usually undetectable. As there are polymorphisms in both of these genes, we have now analyzed whether there are allelic associations between these loci and whether these would have an influence on plasma IL‐1Ra levels. In 200 healthy blood donors, the mean plasma IL‐1Ra concentration was 681 pg/ml. The IL‐1Ra allele 2 (IL1RN*2) had a clear influence on IL‐1Ra levels: its carriers had higher levels than the non‐carriers (745 ng/ml vs. 627 pg/ml, p < 0.05, t ‐test). As marker alleles for IL‐1β we used two biallelic base‐exchange polymorphisms (at positions − 511 and + 3953 relative to the transcriptional start site). The more rare allele of IL‐1β − 511 (allele 2) was significantly associated with the presence of IL‐1Ra allele 2, but in the case of the IL‐1β + 3953, the more rare allele (allele 2) was less frequent in the carriers of the IL‐1Ra allele 2. These IL‐1β allelisms did not have a direct influence on plasma IL‐1Ra levels, but the enhancing effect of IL‐1Ra allele 2 on IL‐1Ra plasma levels required the presence of the IL‐1β − 511 allele 2 or absence of the IL‐1β + 3953 allele 2. Taken together, these results indicate that the IL‐1β gene participates in the regulation of IL‐1Ra production in vivo and that the alleles of IL‐1β and IL‐1Ra which demonstrate this cooperative effect are often associated.

Interleukin‐10 generation in atopic children following oral Lactobacillus rhamnosus GG

Oral Lactobacillus rhamnosus GG ingestion for 5 days to 4 weeks has been shown to alleviate clinical symptoms of gastrointestinal inflammation and atopic dermatitis.

Down‐Regulation of Anti‐CD3 Antibody‐Induced IL‐4 Production by Bovine Caseins Hydrolysed with Lactobacillus GG‐Derived Enzymes

A prerequisite for systemic hyporesponsiveness to dietary antigens is their processing in the gut. This study investigated whether bovine caseins degraded by enzymes of an intestinal bacterial strain, Lactobacillus GG (ATCC 53103), could regulate the cytokine production by anti‐CD3 antibody‐induced peripheral blood mononuclear cells of 14 atopic patients, aged 5–29 (mean, 16) months. Purified casein up‐regulated the interleukin‐4 and interferon‐γ production, P = 0.008 and P = 0.008, respectively. Conversely, Lactobacillus GG‐degraded casein down‐regulated the interleukin‐4 production, P = 0.003, with no effect on interferon‐γ. These results indicate that intestinal bacteria may modify immunomodulatory properties of native food proteins and introduce a promising tool to provide protection from potentially harmful dietary antigens at a young age.

Polymorphism of the Interleukin-10 Gene Is Associated with Susceptibility to Epstein-Barr Virus Infection

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.

Interleukin-6 and interleukin-1 receptor antagonist in cerebrospinal fluid from patients with recent tonic-clonic seizures

We have previously reported increased concentrations of interleukin (1L)-6 in CSF from patients with tonic-clonic seizures, where increased cytokine production most likely is a consequence of neuronal epileptic activity associated with seizures. The biological effects of IL-6 are mediated by other cytokines, which are studied here in addition to IL-6. The purpose of this study was to analyze levels of soluble cytokines from plasma and CSF from patients with newly developed tonic-clonic seizures. The concentrations of IL-6, IL-1 receptor antagonist (IL-1RA), IL-1beta, tumor necrosis factor (TNFalpha) and nerve growth factor (NGF) were measured from plasma and CSF from 22 patients with newly developed tonic-clonic seizures within 24 h from the seizure and 18 controls. The mean concentrations of IL-6 were significantly increased in CSF (P<0.001) and plasma (P<0.01) after tonic-clonic seizures, there was some indication of increased concentrations of IL-1RA and no significant change in NGF, IL-1beta or TNFalpha. Our study shows that cytokine network is activated in patients after recent tonic-clonic seizures. We provide evidence of intrathecal production of IL-6 associated with electrical seizure activity.

Gene polymorphisms of interleukins 1 and 10 in infectious and autoimmune diseases

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.

Increased Plasma Levels of Pro‐ and Anti‐inflammatory Cytokines in Patients with Febrile Seizures

Summary:  Purpose: Pro‐ and antiinflammatory cytokines regulate the febrile response during infection. Febrile seizures (FSs) conversely are associated with rapid onset of high fever. Activation of the cytokine network has been shown in previous studies of FSs and cytokines. In this study, the association between cytokines and FSs was further investigated.

Polymorphisms of the interleukin-1 gene complex in schizophrenia.

Activation of the inflammatory response system has been related to the pathophysiology of schizophrenia by several recent studies. Schizophrenic patients have varied levels of proinflammatory cytokines, such as interleukin (IL)-1,-6, and tumor necrosis factor (TNF)α in their peripheral blood or cerebrospinal fluid.1–6 These cytokines can modify the metabolism of neurotransmitters, influence neural development, and IL-1 has been implicated in acute, and, on the other hand, chronic neurodegeneration.7,8 They could therefore be of primary pathogenic importance, either in the acute disease or during those stages of brain development which possibly influence the sensitivity of a person to schizophrenia in later life. The cytokine regulation of brain development and its possible neuroimmune involvement in the pathogenesis of schizophrenia has been raised.9 One indication of the pathogenic role of IL-1 in schizophrenia would be a demonstration of the difference between schizophrenic patients and healthy controls at the gene level. Therefore we analyzed the polymorphism of the IL-1 gene complex in 50 schizophrenic patients and in 400 healthy blood donors. The following allelisms were analyzed: IL-1β gene: base exchange polymorphisms at the positions −511 (relative to the transcriptional start site); IL-1α gene: base exchange polymorphism at the position −889; IL-1 receptor antagonist (IL-1RA) gene: variable numbers of 86-base pair tandem repeats in intron 2. The frequencies of the IL-1β (−511) allele 1, IL-1α (−889) allele 2, and IL-1RA allele 1 were somewhat, but not significantly, higher in the schizophrenic patients as compared to the controls. These alleles are known to be located on the same haplotype.10 The number of carriers of this haplotype was significantly higher in the schizophrenia patients (17/50 vs 81/400) than in the controls (P = 0.026, χ2). The frequencies of this haplotype were 0.38 and 0.27, respectively (P = 0.0266, χ2). The number of homozygotes of this haplotype was significantly higher in the schizophrenia patients (P = 0.0006, χ2). These data suggest that the cytokine aberrations in schizophrenia are, at least partly, genetically determined.

A combination of three common inherited mitochondrial DNA polymorphisms promotes longevity in Finnish and Japanese subjects

Mitochondrial DNA (mtDNA) coding region polymorphisms, as well as the 150T polymorphism in the noncoding region, have been associated with longevity. We have studied here the association of 150T with longevity further and assessed differences in this association between various mtDNA haplogroups. We analysed a sample of 321 very old subjects and 489 middle-aged controls from Finland and Japan. 150T was more frequent among the very old than among the controls in both the Finnish and Japanese subjects. Interestingly, the association was not similar in all haplogroups, and a stratified analysis revealed that two additional common polymorphisms, 489C and 10398G, modified the association between 150T and longevity. These findings suggest that longevity is partly determined by epistatic interactions involving these three mtDNA loci.

Polymorphisms within the tumor necrosis factor locus and prevalence of coronary artery disease in middle-aged men

Tumor necrosis factor (TNF) is an important cytokine in the inflammation process of atherosclerosis and is also involved in lipid metabolism. Two biallelic polymorphisms within TNF gene locus-TNFA at the position -308 in the promoter region of the TNF gene and TNFB in the first intron of the lymphotoxin-alpha (LT-alpha) have been reported to be associated with TNF production and with susceptibility to inflammatory diseases. We studied the association of these polymorphisms within the major histocompatibility complex (MHC) III region with coronary atherosclerosis and its manifestations. The autopsy series comprised 700 Caucasian Finnish men, aged 33-70 years (The Helsinki Sudden Death Study). Coronary stenosis and surface area of atherosclerotic changes (fatty streaks, fibrous plaques, complicated lesions and calcification) were measured and the presence of myocardial infarction and coronary thrombosis recorded. TNFA and TNFB genotypes were determined by the PCR-RFLP technique. The allele frequencies were TNFA1/TNFA2=0.88/0.12 and TNFB1/TNFB2=0.30/0.70. There was a strong linkage disequilibrium between the two polymorphisms. There were no differences in coronary stenosis and in the frequency of old or recent myocardial infarction or coronary thrombosis between men with different genotype status in either locus. Men with TNFA22 or TNFB11 genotype tended to have more fibrous lesions and calcification in their coronary arteries. TNFA and TNFB polymorphisms are unlikely to contribute to progression of atherosclerosis in a way clinically important.