Fatigue in patients with plaque-type psoriasis: lack of an association with plasma cytokines.

BACKGROUND: Fatigue is common in patients with psoriasis, and cytokines have been postulated to influence fatigue. OBJECTIVES: This case-control study explored the plasma levels of selected cytokines in patients with psoriasis and compared them with fatigue and other clinical factors. MATERIALS AND METHODS: Eighty-four patients with chronic plaque-type psoriasis and 84 age- and gender-matched healthy subjects were enrolled. Psoriasis severity was measured using the Psoriasis Area and Severity Index (PASI), and skin-related quality of life using the Dermatology Life Quality Index (DLQI). Fatigue was rated with the fatigue Visual Analogue Scale (fVAS). Plasma levels of interleukin (IL)-1ß, IL-1Rα, IL-1RII, IL-6, and IL-10 were measured by electrochemiluminescence sandwich immunoassay and ELISA. RESULTS: IL-1Rα and IL-6 median concentrations were significantly higher in patients than healthy subjects: 203 pg/mL (interquartile range: 150-274) versus 166 pg/mL (128-212), p=0.008 for IL-Rα, and 0.82 pg/mL (0.25-1.40) versus 0.50 pg/mL (0.25-0.91), p=0.009 for IL-6. IL-1ß, IL-1RII, and IL-10 concentrations did not differ between patients and healthy subjects. Higher levels of IL-1Rα and IL-6 were associated with increased body mass index (BMI), but not with disease activity. Cytokine concentrations were not associated with fatigue. CONCLUSION: These findings do not support an association between fatigue and blood concentrations of selected pro- and anti-inflammatory cytokines. The increased IL-1Rα and IL-6 levels associated with increased BMI are probably caused by release of adipokines from adipose tissue; of these, leptin, in particular, is known to be a strong inflammatory stimulator.

Soluble IL-1 receptor 2 is associated with left ventricular remodelling in patients with ST-elevation myocardial infarction.

BACKGROUND: The inflammatory response following myocardial infarction (MI) is prerequisite for proper healing of infarcted tissue, but can also have detrimental effects on cardiac function. Interleukin (IL)-1α and IL-1ß are potent inflammatory mediators and their bioactivity is tightly regulated by IL-1 receptor antagonist (IL-1ra) and soluble (s) IL-1 receptors (R). We aimed to examine whether levels of soluble regulators of IL-1 signalling are changed during ST-elevation MI (STEMI) and their associations with parameters of cardiac injury and ventricular remodelling. METHODS: Plasma levels of IL-1Ra, sIL-1R1, sIL-1R2 and sIL-1R accessory protein (sIL-1RAcP) were measured by immunoassays in repeated samples from patients with STEMI (n = 255) and compared to healthy controls (n = 65). RESULTS: IL-1Ra, sIL-1R1 and sIL-1R2 levels were all significantly elevated after STEMI, while levels of sIL-1RAcP were lower compared to controls. sIL-1R2 levels (at different time points) correlated positively with C-reactive protein, myocardial infarct size and change in indexed left ventricular end-diastolic and end-systolic volume (LVEDVi and LVESVi) measured by cardiac MR acutely and after 4 months, and negatively with LV ejection fraction. Patients with >median levels of sIL-1R2 in the acute phase were more likely to have increased change in LVEDVi and LVESVi. Importantly, sIL-1R2 remained significantly associated with change in LVEDVi and LVESVi also after adjustment for clinical covariates. CONCLUSION: Levels of sIL-1R2 are independently associated with parameters of LV adverse remodelling following STEMI.

IL-1 family cytokines and receptors in IgG4-related disease.

BACKGROUND/AIM: The IgG4-related disease (IgG4-RD) is a fibroinflammatory condition that can affect almost any organ, often associated with eosinophilia and increased levels of IgE and IgG4. Overexpression in tissues of Th2-related cytokines but also of IFN-γ has been reported. Given the major role of Il-1 family cytokines in inducing and regulating inflammation, and the paucity of data so far available in IgG-RD, we performed a comprehensive analysis of IL-18, related IL-1 family cytokines and soluble receptors in these patients. PATIENTS AND METHODS: Fifteen patients fulfilling the criteria for the diagnosis of IgG4-RD and 80 blood donors as control were recruited. Cytokines of the IL-1 family (IL-1α, IL-1ß, IL-33, IL-18), soluble receptors (sIL-1R1, sIL-1R2, sIL-1R3, ST2/sIL-1R4) and antagonists (IL-1Ra, IL-18 binding protein -IL-18BP-) were measured in sera by multiarray ELISA assay. Free IL-18 was calculated as the amount of IL-18 not inhibited by IL-18BP. RESULTS: Half of the patients had a multiorgan disease, mainly affecting retroperitoneum, lymph nodes and pancreas. sIL-1R1 (p=0.0001), sIL-1R2 (p=0.0024), ST2/sIL-1R4 (p=0.002) were significantly increased in IgG4-RD sera compared with healthy controls; sIL-R3 was significantly lower in patients vs controls (p=0,0006). CONCLUSIONS: The increased levels of the soluble forms of the two IL-1 receptors IL-1R1 and IL-1R2 suggest the need to dampen IL-1-mediated inflammation at the tissue level. Elevated circulating ST2/sIL-1R4 levels may represent the marker of an ongoing protective mechanism, but their contribution to organ damage cannot be excluded. On the whole, the data suggest a tight control of IL-1 family cytokines signalling in IgG4-RD.

Expression of Interleukin-1 and Interleukin-1 Receptors Type 1 and Type 2 in Hodgkin Lymphoma.

Signaling through the IL-1-receptor type 1 (IL-1R1), IL-1 is required for initiation and maintenance of diverse activities of the immune system. A second receptor, IL-1R2, blocks IL-1 signal transduction. We studied expression of IL-1beta, IL-1R1, and IL-1R2 in 17 Hodgkin lymphomas (HL) by in situ hybridization (ISH). IL-1beta expressing cells, morphologically consistent with endothelial cells and fibroblasts, occurred in all HL tissues with elevated transcript levels in areas of active fibrosis. Hodgkin and Reed-Sternberg (HRS) cells of all cases expressed low IL-1R1 transcript levels in some tumor cells, and high levels of IL-1R2 in large proportions of HRS cells. Only few bystander cells showed low levels of IL-1R1 and IL-1R2 RNA. Supernatants of 4 out of 7 HL-derived cell lines contained soluble IL-1R2 protein at high levels. HL patient sera carried variably amounts of IL-1R2 protein with significantly increased titers in patients with active disease compared to patients in complete remission and control individuals without HL. Western blots and co-immunoprecipitations showed binding of the IL-1R2 to the intracellular IL-1R-accessory protein (IL-1IRAcP). These data suggest functions of the IL-1R2 as a "decoy-receptor" sequestrating paracrine IL-1 extracellularly and intracellularly by engaging IL-1IRAcP, thus depriving IL1-R1 molecules of their extracellular and intracellular ligands. Expression of IL1-R2 by HRS cells seems to contribute to local and systemic modulation of immune function in HL.

Deficient cytokine control modulates temporomandibular joint pain in rheumatoid arthritis.

The aim was to investigate how endogenous cytokine control of tumor necrosis factor (TNF) influences temporomandibular joint (TMJ) pain in relation to the role of anti-citrullinated peptide antibodies (ACPA) in patients with rheumatoid arthritis (RA). Twenty-six consecutive patients with TMJ RA were included. Temporomandibular joint pain intensity was assessed at rest, on maximum mouth opening, on chewing, and on palpation. Mandibular movement capacity and degree of anterior open bite (a clinical sign of structural destruction of TMJ tissues) were also assessed. Systemic inflammatory activity was assessed using the Disease Activity Score in 28 joints (DAS28) for rheumatoid arthritis. Samples of TMJ synovial fluid and blood were obtained and analyzed for TNF, its soluble receptor, soluble TNF receptor II (TNFsRII), and ACPA. A high concentration of TNF in relation to the concentration of TNFsRII in TMJ synovial fluid was associated with TMJ pain on posterior palpation on maximum mouth opening. The ACPA concentration correlated significantly to the TNF concentration, but not to the TNFsRII concentration, indicating that increased inflammatory activity is mainly caused by an insufficient increase in anti-inflammatory mediators. This study indicates that TMJ pain on palpation in patients with RA is related to a deficiency in local cytokine control that contributes to increased inflammatory activity, including sensitization to mechanical stimuli over the TMJ.

Microarray analysis identifies IL-1 receptor type 2 as a novel candidate biomarker in patients with acute respiratory distress syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a disease associated with a high mortality rate. The initial phase is characterized by induction of inflammatory cytokines and chemokines and influx of circulating inflammatory cells, including macrophages which play a pivotal role in the innate and adaptive immune responses to injury. Growing evidence points to phenotypic heterogeneity and plasticity between various macrophage activation states. METHODS: In this study, gene expression in alveolar macrophages and circulating leukocytes from healthy control subjects and patients with ARDS was assessed by mRNA microarray analysis. RESULTS: Both alveolar macrophages and circulating leukocytes demonstrated up-regulation of genes encoding chemotactic factors, antimicrobial peptides, chemokine receptors, and matrix metalloproteinases. Two genes, the pro-inflammatory S100A12 and the anti-inflammatory IL-1 decoy receptor IL-1R2 were significantly induced in both cell populations in ARDS patients, which was confirmed by protein quantification. Although S100A12 levels did not correlate with disease severity, there was a significant association between early plasma levels of IL-1R2 and APACHE III scores at presentation. Moreover, higher levels of IL-1R2 in plasma were observed in non-survivors as compared to survivors at later stages of ARDS. CONCLUSIONS: These results suggest a hybrid state of alveolar macrophage activation in ARDS, with features of both alternative activation and immune tolerance/deactivation.. Furthermore, we have identified a novel plasma biomarker candidate in ARDS that correlates with the severity of systemic illness and mortality.

Relationship between interleukin-1 type 1 and 2 receptor gene polymorphisms and the expression level of membrane-bound receptors.

The biological activity of the multifunctional cytokine interleukin-1 (IL-1) is mediated by its receptors. The aim of this study was to determine if an association exists between single nucleotide polymorphisms (SNPs) in the IL-1 type 1 and 2 receptor genes (IL1R1 and IL1R2) and the expression level of membrane-bound IL1Rs on subpopulations of mononuclear cells or serum levels of soluble IL-1 receptors. It was observed that healthy individuals with the genotype TT in SNP rs2234650:C>T had a lower percentage of intact CD14(+) monocytes expressing IL1R1 on their surface. The SNP rs4141134:T>C in IL1R2 has also been associated with the percentage of intact CD3(+) T cells expressing IL1R2. Furthermore, individuals carrying the CC allele of SNP rs4141134:T>C and the TT allele of SNP rs2071008:T>G in IL1R2 had a lower density of IL1R2s on the surface of CD14(+) monocytes in lipopolysaccharide (LPS)-stimulated PBMC cultures. In summary, this study demonstrated that IL-1 receptor gene polymorphisms could be one of the factors influencing the expression of membrane-bound IL-1 receptors (IL1R) on immunocompetent cells.

[Endometriosis: increasing concentrations of serum interleukin-1ß and interleukin-1sRII is associated with the deep form of this pathology]. / Endométriose: l'augmentation des concentrations d'interleukine-1ß et d'interleukine-1sRII dans le sérum est associée à la forme profonde de cette pathologie.

OBJECTIVES: To assess interleukin-1ß (IL-1ß) and its inhibitory soluble interleukin-1 receptor type II (IL-1sRII) levels into the serum of patients with various forms of endometriosis and normal women, and investigate the correlation with disease activity. PATIENTS AND METHODS: In this prospective laboratory study (2005-2010), 510 women with histologically proven endometriosis and 93 endometriosis-free controls have been enrolled. Laparoscopic complete exploration of the abdominopelvic cavity and blood samples have been performed in each patient. For each serum, IL-1ß and IL-1sRII have been evaluated using Elisa. RESULTS: IL-1ß and IL-1sRII have been respectively detectable in 64% and 54.6% of serum samples from all 603 women studied. IL-1ß was higher in women with deep infiltrating endometriosis (DIE) (mean 10.0pg/mL [0.005-416.2]) than in endometriosis-free women (mean 0.5pg/mL [0.01-1.7], P<0.01) or in women with superficial endometriosis (SUP) (mean 0.6pg/mL [0.1-2.9], P<0.01). Also, IL-1sRII was higher in DIE (mean 236.7pg/mL [0.9-6975]) than in the witness group (mean 85.0pg/mL [1-235.2], P<0.05) or in SUP (mean 85.1pg/mL [0.6-302], P<0.01). CONCLUSION: This study highlights both a marked significant increase in serum IL-1ß and IL-1sRII levels in DIE compared to SUP and normal women and suggests that a defect in the control of IL-1 can impact the pathophysiology of endometriosis.

Echocardiography, spirometry, and systemic acute-phase inflammatory proteins in smokers with COPD or CHF: an observational study.

Chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) may coexist in elderly patients with a history of smoking. Low-grade systemic inflammation induced by smoking may represent the link between these 2 conditions. In this study, we investigated left ventricular dysfunction in patients primarily diagnosed with COPD, and nonreversible airflow limitation in patients primarily diagnosed with CHF. The levels of circulating high-sensitive C-reactive protein (Hs-CRP), pentraxin 3 (PTX3), interleukin-1ß (IL-1 ß), and soluble type II receptor of IL-1 (sIL-1RII) were also measured as markers of systemic inflammation in these 2 cohorts. Patients aged ≥ 50 years and with ≥ 10 pack years of cigarette smoking who presented with a diagnosis of stable COPD (n=70) or stable CHF (n=124) were recruited. All patients underwent echocardiography, N-terminal pro-hormone of brain natriuretic peptide measurements, and post-bronchodilator spirometry. Plasma levels of Hs-CRP, PTX3, IL-1 ß, and sIL-1RII were determined by using a sandwich enzyme-linked immuno-sorbent assay in all patients and in 24 healthy smokers (control subjects). Although we were unable to find a single COPD patient with left ventricular dysfunction, we found nonreversible airflow limitation in 34% of patients with CHF. On the other hand, COPD patients had higher plasma levels of Hs-CRP, IL1 ß, and sIL-1RII compared with CHF patients and control subjects (p < 0.05). None of the inflammatory biomarkers was different between CHF patients and control subjects. In conclusion, although the COPD patients had no evidence of CHF, up to one third of patients with CHF had airflow limitation, suggesting that routine spirometry is warranted in patients with CHF, whereas echocardiography is not required in well characterized patients with COPD. Only smokers with COPD seem to have evidence of systemic inflammation.

The association between endometriosis and polymorphisms in the interleukin-1 family genes in Korean women.

PROBLEM: To investigate the association between polymorphisms of the interleukin-1 (IL-1) family genes and endometriosis in Korean women. METHOD OF STUDY: In this case-control study, the IL-1α -889C>T, IL-1 receptor antagonist (IL-1RA) 86-bp microsatellite, IL-1 receptor 1 (IL-1R1) 52C>A, 294C>T, 1498T>C, 1632A>G, IL-1R2 rs2072472 C>T and rs7561460 C>T polymorphisms were analyzed in women with (n = 138) and without (n = 214) endometriosis using restriction fragment length polymorphism (RFLP) analysis, TaqMan assay, or DNA sequencing. Serum IL-1α, soluble IL-1RA (sIL-1RA), and sIL-1R2 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Among the polymorphisms measured, the 1498T>C polymorphisms in the IL-1R1 gene were found to be related with early-stage endometriosis but not with advanced-stage endometriosis. The genotypes with at least one T allele (CT + TT) were less frequently observed in early-stage endometriosis compared with normal controls (OR = 0.44, 95% CI = 0.22-0.87, P = 0.02). Serum sIL-1R2 levels were significantly lower (P < 0.01) in women with endometriosis than in normal controls, whereas no difference in serum sIL-1RA levels between these two groups was noted. The single and haplotype genotypes of the IL-1R2 and IL-1RA microsatellite polymorphisms were not related with these serum levels. CONCLUSION: The IL-1R1 1498T>C polymorphism is associated with early-stage endometriosis in Korean women.

Blood-based biomarkers can differentiate ulcerative colitis from Crohn's disease and noninflammatory diarrhea.

BACKGROUND: Blood gene expression profiling has been used in several studies to identify patients with a number of conditions and diseases. A blood test with the ability to differentiate Crohn's disease (CD) from ulcerative colitis (UC) and noninflammatory diarrhea would be useful in the clinical management of these diseases. METHODS: Affymetrix U133Plus 2.0 GeneChip oligonucleotide arrays were used to generate whole blood gene expression profiles for 21 patients with UC, 24 patients with CD, and 10 control patients with diarrhea, but without colonic pathology. RESULTS: A supervised learning method (logistic regression) was used to identify specific panels of probe sets which were able to discriminate between UC and CD and from controls. The UC panel consisted of the four genes, CD300A, KPNA4, IL1R2, and ELAVL1; the CD panel comprised the four genes CAP1, BID, NIT2, and NPL. These panels clearly differentiated between CD and UC. CONCLUSIONS: Gene expression profiles from blood can differentiate patients with CD from those with UC and from noninflammatory diarrheal disorders.

Soluble IL-1RII and IL-18 are associated with incipient upper extremity soft tissue disorders.

Previous studies suggest a role for IL-1ß in the pathophysiology of upper extremity soft tissue disorders (UESTDs). We studied the levels of interleukin-1 family members in patients with incipient UESTDs and compared them with healthy controls. In this case control study, we included 163 patients with UESTDs and symptom duration shorter than 1 month and 42 healthy controls matched for age and gender at the group level. Serum levels of cytokines IL-1α, IL-1ß, IL-1Ra, IL-6, IL-8, IL-18, IL-33, TNFα and sensitized C-reactive protein as well as IL-1 family soluble receptors sIL-1RII and sST2 were assessed. We used unconditional logistic regression models to study the associations between cytokines and UESTDs. After adjustment for potential confounders, the serum levels of sIL-1RII (p<0.001) and sST2 (p=0.014) were higher in the patients than the controls. The level of IL-18 was lower in the patients than the controls (p=0.005). There were no significant differences between the patients and controls regarding the levels of IL-1α, IL-1ß, IL-1Ra, IL-33, IL-6, IL-8, TNFα, or sensitized C-reactive protein. The levels of circulating sIL-1RII and IL-18 are associated with incipient UESTDs, suggesting an important role for these IL-1 family members in the early course of UESTDs.

Temporomandibular joint pressure pain threshold is systemically modulated in rheumatoid arthritis.

AIMS: To investigate the relative importance of systemic and local inflammatory mediators (serotonin: 5-HT; tumor necrosis factor: TNF; soluble interleukin-1 receptor II: IL-1sRII) in the modulation of temporomandibular joint (TMJ) pressure pain threshold in patients with seropositive or seronegative rheumatoid arthritis (RA) and to investigate to what extent TMJ pressure pain threshold is related to other TMJ pain parameters. METHODS: Sixty patients with seropositive RA for rheumatoid factor and 74 patients with seronegative RA involving the TMJ were investigated regarding synovial fluid and plasma levels of IL-1sRII, 5-HT, and TNF as well as erythrocyte sedimentation rate, C-reactive protein, thrombocyte particle count, and rheumatoid factor in blood. TMJ resting pain, movement pain, tenderness, and palpebral pain reflex to digital palpation and TMJ pressure pain threshold were examined. RESULTS: Statistical analyses indicated that TMJ pressure pain threshold was only correlated to systemic factors. TMJ movement pain was in turn mainly correlated to systemic mediators in the seropositive patients but to local mediators in the seronegative patients where synovial fluid IL-1sRII was positively correlated to TMJ pain on mouth opening. Seropositive patients had higher systemic inflammatory activity but lower TMJ movement pain intensities than seronegative patients. CONCLUSION: The results indicate that TMJ pressure pain threshold is modulated by systemic rather than local inflammatory mediators and suggest that it is unrelated or only weakly related to other TMJ pain entities in RA patients. A rheumatoid factor-dependent systemic modulation, in combination with local factors, seems to account for TMJ pain in RA patients.

Impaired counter-regulation of interleukin-1 by the soluble IL-1 receptor type II in patients with chronic liver disease.

OBJECTIVE: To assess the production of the endogenous IL-1 modulators IL-1 receptor antagonist (IL-1Ra), type I and II soluble IL-1 receptors (IL-1sRI and II) in patients with chronic liver disease (CLD). MATERIAL AND METHODS: Plasma levels of IL-1beta (IL-1beta) and IL-1 modulators were assessed in 126 CLD patients and 39 healthy controls. IL-1sRII was also measured in the supernatants of primary hepatocyte cultures. RESULTS: Plasma IL-1sRI and IL-1Ra levels were significantly higher in cirrhotic CLD patients than in non-cirrhotic CLD patients and in controls. Levels did not depend on the etiology of CLD. Likewise, plasma IL-1beta levels were elevated in CLD patients compared with those in controls. In contrast, IL-1sRII levels did not differ between CLD patients and controls. Cultures of human primary hepatocytes showed that IL-1sRII is induced by IL-1beta, but not IL-6. CONCLUSIONS: In cirrhotic CLD patients elevated plasma IL-1beta is not counteracted by endogenous levels of IL-1sRII, whereas high IL-1sRI is expected to neutralize the naturally occurring antagonist IL-1Ra, resulting in a dysregulation of the IL-1 system that might enhance pro-inflammatory activity of IL-1.

Transcriptional signals of T-cell and corticosteroid-sensitive genes are associated with future acute cellular rejection in cardiac allografts.

BACKGROUND: Profiling mRNA levels of 11 informative genes expressed by circulating immune effector cells identifies cardiac allograft recipients at low risk for current moderate-severe acute cellular rejection (ACR). METHODS: We conducted a nested case-control study of 104 cardiac allograft recipients to investigate the association of transcriptional profiles of blood samples with either a future rejection episode within 12 weeks of a baseline clinical sample or persistent histologic quiescence for the same time period. RESULTS: The transcription profile yielded a score (0 to 40 scale) of 27.4 +/- 6.3 for future rejectors (n = 39) and 23.9 +/- 7.1 for controls (n = 65) (p = 0.01). In patients who were

Polymorphisms in cytokine genes influence long-term survival differently in elderly male and female patients.

OBJECTIVES: We asked if single nucleotide polymorphisms (SNP) in inflammatory cytokine genes related to 3-year survival in ill elderly subjects and if genotypes differed between the elderly and a younger control population. DESIGN: Prospective observational study. SETTING: Two geriatric departments at a university hospital. SUBJECTS: Eighty three acutely admitted geriatric patients (83 +/- 7 year, 70% women) and 207 young healthy subjects (40 +/- 1 year, 37% women) were included. OUTCOME MEASURES: Single nucleotide polymorphisms in the genes of tumour necrosis factor (TNF)-alpha-308 G/A, interleukin (IL)-1beta-511 C/T, IL-6-174 G/C and IL-10-1082 A/G were analysed. In the geriatric patients SNP in lymphotoxin (LT)-alpha +252 G/A and serum levels of TNF-alpha, IL-6, IL-10, soluble IL-I receptor(R)II were also determined, as well as the 3-year mortality. RESULTS: The allele distribution did not differ significantly between the elderly and the young. In the female elderly, 3-year survival was doubled (P < 0.05) in those with the high-producing genotypes of IL-6 -174 GG and TNF-alpha -308 GA compared with those with low-producing alleles. In contrast, men with high-producing LT-alpha +252 AA and IL-1beta-511 CT&TT genotypes displayed halved 3-year survival (P < 0.05) compared with those with low-producing genotypes, whereas possession of the high-producing IL-10 -1082 GG genotype favoured survival. Serum IL-10 was higher in the high-producing IL-10 genotype in females. CONCLUSION: As high-producing IL-6 -174 genotype favoured 3-year survival in women, whereas the likewise high-producing LT-alpha +252 and IL-1beta -511 genotypes were associated with poor survival in men, we conclude that the specific genotypes, in association with gender, may act as determinants for survival in elderly patients.