Browsing by Subject "INTERLEUKIN-6"

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  • Huusko, Johanna M.; Karjalainen, Minna K.; Mahlman, Mari; Haataja, Ritva; Kari, M. Anneli; Andersson, Sture; Toldi, Gergely; Tammela, Outi; Ramet, Mika; Lavoie, Pascal M.; Hallman, Mikko (2014)
  • Pekkala, Satu; Keskitalo, Anniina; Kettunen, Emilia; Lensu, Sanna; Nykänen, Noora; Kuopio, Teijo; Ritvos, Olli; Hentilä, Jaakko; Nissinen, Tuuli A.; Hulmi, Juha J. (2019)
    Colorectal cancer (CRC) and cachexia are associated with the gut microbiota and microbial surface molecules. We characterized the CRC-associated microbiota and investigated whether cachexia affects the microbiota composition. Further, we examined the possible relationship between the microbial surface molecule flagellin and CRC. CRC cells (C26) were inoculated into mice. Activin receptor (ACVR) ligands were blocked, either before tumor formation or before and after, to increase muscle mass and prevent muscle loss. The effects of flagellin on C26-cells were studied in vitro. The occurrence of similar phenomena were studied in murine and human tumors. Cancer modulated the gut microbiota without consistent effects of blocking the ACVR ligands. However, continued treatment for muscle loss modified the association between microbiota and weight loss. Several abundant microbial taxa in cancer were flagellated. Exposure of C26-cells to flagellin increased IL6 and CCL2/MCP-1 mRNA and IL6 excretion. Murine C26 tumors expressed more IL6 and CCL2/MCP-1 mRNA than C26-cells, and human CRC tumors expressed more CCL2/MCP-1 than healthy colon sites. Additionally, flagellin decreased caspase-1 activity and the production of reactive oxygen species, and increased cytotoxicity in C26-cells. Conditioned media from flagellin-treated C26-cells deteriorated C2C12-myotubes and decreased their number. In conclusion, cancer increased flagellated microbes that may promote CRC survival and cachexia by inducing inflammatory proteins such as MCP-1. Cancer-associated gut microbiota could not be rescued by blocking ACVR ligands.
  • Filppu, Pauliina; Ramanathan, Jayendrakishore Tanjore; Granberg, Kirsi J.; Gucciardo, Erika; Haapasalo, Hannu; Lehti, Kaisa; Nykter, Matti; Le Joncour, Vadim; Laakkonen, Pirjo (2021)
    Glioma stem cells (GSCs) drive propagation and therapeutic resistance of glioblastomas, the most aggressive diffuse brain tumors. However, the molecular mechanisms that maintain the stemness and promote therapy resistance remain poorly understood. Here we report CD109/STAT3 axis as crucial for the maintenance of stemness and tumorigenicity of GSCs and as a mediator of chemoresistance. Mechanistically, CD109 physically interacts with glycoprotein 130 to promote activation of the IL-6/STAT3 pathway in GSCs. Genetic depletion of CD109 abolished the stemness and self-renewal of GSCs and impaired tumorigenicity. Loss of stemness was accompanied with a phenotypic shift of GSCs to more differentiated astrocytic-like cells. Importantly, genetic or pharmacologic targeting of CD109/STAT3 axis sensitized the GSCs to chemotherapy, suggesting that targeting CD109/STAT3 axis has potential to overcome therapy resistance in glioblastoma.
  • Nieminen, Anne; Maksimow, Mikael; Mentula, Panu; Kyhala, Lea; Kylänpää, Leena; Puolakkainen, Pauli; Kemppainen, Esko; Repo, Heikki; Salmi, Marko (2014)
  • Peltonen, Reetta; Gramkow, Mathias H.; Dehlendorff, Christian; Osterlund, Pia J.; Johansen, Julia S.; Isoniemi, Helena (2020)
    Background The inflammatory biomarkers, YKL-40 and interleukin-6 (IL-6), are elevated in patients with metastatic colorectal cancer. We examined their associations with relapse-free survival and overall survival in combination with serum C-reactive protein (CRP), carcinoembryonic antigen (CEA), and carbohydrate antigen 19–9 (CA19-9) in patients with colorectal liver metastases. Methods Altogether 441 consecutive patients undergoing liver resection at Helsinki University Hospital between 1998 and 2013 were included in the study. Pre- and postoperative YKL-40 and IL-6 were determined from serum samples with commercially available enzyme-linked immunosorbent assay (ELISA) kits, and CRP, CEA, and CA19-9 by routine methods. Associations between these biomarkers and relapse-free and overall survival were examined using Cox regression analysis. Results Patients with 2–5 elevated biomarkers were at an increased risk of relapse compared to those with 0–1 elevated biomarkers, preoperatively (HR 1.37, 95% CI 1.1–1.72) or postoperatively (HR 1.54, 95% CI 1.23–1.92). Patients with 2–5 elevated biomarkers were also at an increased risk of death compared to those with 0–1 elevated biomarkers, preoperatively (HR 1.76, 95% CI 1.39–2.24) or postoperatively (HR 1.83, 95% CI 1.44–2.33). Conclusion The results suggest that a protein panel of the inflammatory biomarkers YKL-40, IL-6, and CRP, and the cancer biomarkers CEA and CA19-9 might identify patients that benefit from more aggressive treatment and surveillance, although the additional value of IL-6 and CRP in this aspect is limited.
  • Borges, Alvaro H.; O'Connor, Jemma L.; Phillips, Andrew N.; Baker, Jason V.; Vjecha, Michael J.; Losso, Marcelo H.; Klinker, Hartwig; Lopardo, Gustavo; Williams, Ian; Lundgren, Jens D.; INSIGHT SMART Study Grp; ESPRIT Study Grp; SILCAAT Sci Comm; Ristola, Matti A (2014)
  • Mantula, Paula S.; Outinen, Tuula K.; Jaatinen, Pia; Hämäläinen, Mari; Huhtala, Heini; Pörsti, Ilkka H.; Vaheri, Antti; Mustonen, Jukka T.; Mäkelä, Satu M. (2018)
    Background Puumala hantavirus (PUUV) infected patients typically suffer from acute kidney injury (AKI). Adipokines have inflammation modulating functions in acute diseases including AKI. We examined plasma levels of three adipokines (resistin, leptin, and adiponectin) in acute PUUV infection and their associations with disease severity. Methods This study included 79 patients hospitalized due to acute PUUV infection. Plasma resistin, leptin, adiponectin, as well as IL-6 and CRP, were measured at the acute phase, recovery phase and one year after hospitalization. Results Plasma resistin levels were significantly higher in the acute phase compared to the recovery phase and one year after (median resistin 28 pg/mL (11-107) vs. 17 pg/mL (7-36) vs. 14 pg/mL (7-31), p= 353.6 mu mol/L) (OR 1.08, 95% CI 1.02-1.14). Neither plasma leptin nor adiponectin level had any correlation with creatinine concentration or the amount of albuminuria. Conclusions Plasma resistin independently associates with the severity of AKI in acute PUUV infection. The association of resistin with the amount of albuminuria suggests that the level of plasma resistin is not only influenced by renal clearance but could have some role in the pathogenesis of AKI during PUUV infection.
  • Kyrklund, Mikael; Kummu, Outi; Kankaanpää, Jari; Akhi, Ramin; Nissinen, Antti; Pauliina Turunen, S.; Pussinen, Pirkko; Wang, Chunguang; Hörkkö, Sohvi (2018)
    Treatment of periodontitis has beneficial effects on systemic inflammation markers that relate to progression of atherosclerosis. We aimed to investigate whether immunization with A hemagglutinin domain (Rgp44) of Porphyromonas gingivalis (Pg), a major etiologic agent of periodontitis, would lead to an antibody response cross-reacting with oxidized low-density lipoprotein (OxLDL) and how it would affect the progression of atherosclerosis in low-density lipoprotein receptor-deficient (LDLR-/-) mice. The data revealed a prominent IgM but not IgG response to malondialdehyde-acetaldehyde modified LDL (MAA-LDL) after Rgp44 and Pg immunizations, implying that Rgp44/Pgand MAA adducts may share cross-reactive epitopes that prompt IgM antibody production and consequently confer atheroprotection. A significant negative association was observed between atherosclerotic lesion and plasma IgA to Rgp44 in Rgp44 immunized mice, supporting further the anti-atherogenic effect of Rgp44 immunization. Plasma IgA levels to Rgp44 and to Pg in both Rgp44-and Pg-immunized mice were significantly higher than those in saline control, suggesting that IgA to Rgp44 could be a surrogate marker of immunization in Pg-immunized mice. Distinct antibody responses in plasma IgA levels to MAA-LDL, to Pg lipopolysaccharides (Pg-LPS), and to phosphocholine (PCho) were observed after Rgp44 and Pg immunizations, indicating that different immunogenic components between Rpg44 and Pg may behave differently in regard of their roles in the development of atherosclerosis. Immunization with Rgp44 also displayed atheroprotective features in modulation of plaque size through association with plasma levels of IL-1 alpha whereas whole Pg bacteria achieved through regulation of antiinflammatory cytokine levels of IL-5 and IL-10. The present study may contribute to refining therapeutic approaches aiming to modulate immune responses and inflammatory/antiinflammatory processes in atherosclerosis.
  • Äyräväinen, Leena; Heikkinen, Anna Maria; Kuuliala, Antti; Ahola, Kirsi; Koivuniemi, Riitta; Laasonen, Leena; Moilanen, Eeva; Hämäläinen, Mari; Tervahartiala, Taina; Meurman, Jukka H.; Leirisalo-Repo, Marjatta; Sorsa, Timo (2018)
    Objective: To study prospectively the association of salivary and serum matrix metalloproteinase (MMP)-8, tissue inhibitor of MMPs (TIMP)-1 and interleukin (IL)-6 with periodontal and systemic inflammation in rheumatoid arthritis (RA). We hypothesized that biomarker concentrations reflect inflammation. Methods: Fifty three early untreated RA (ERA) and 28 chronic RA (CRA) patients, underwent rheumatological and dental examinations at baseline and one year later after starting first conventional or biological disease modifying antirheumatic drug. We included 43 control subjects. Saliva and serum samples were analyzed for MMP-8, TIMP-1 and IL-6. Periodontal health was assessed by bleeding on probing (BOP), pocket depth (PD) and periodontal inflammatory burden index (PIBI); RA disease activity was assessed by disease activity score DAS28. Joint destruction was analyzed by the modified Sharp-van der Heijde (SHS) method. Results: Serum MMP-8 (p <.001; p <.001) and IL-6 (p <.001; p =.002) were significantly higher in CRA vs. other study groups during the study. Salivary MMP-8 (p =.010) and IL-6 (p =.010) were significantly higher in ERA vs. other study groups at baseline. Salivary MMP-8 was associated with periodontal parameters. Conclusion: Elevated serum concentrations of MMP-8 and IL-6 in CRA patients reflected chronic RA, while elevated salivary concentrations of MMP-8 levels in ERA patients reflected increased periodontal inflammation.
  • Lehtomäki, Kaisa; Mustonen, Harri; Kellokumpu-Lehtinen, Pirkko-Liisa; Joensuu, Heikki; Hermunen, Kethe; Soveri, Leena-Maija; Boisen, Mogens Karsbol; Dehlendorff, Christian; Johansen, Julia Sidenius; Haglund, Caj; Österlund, Pia (2021)
    Simple Summary Colorectal cancer is the third most common cancer worldwide. Recurrence risk after curative intent surgery combined with adjuvant chemotherapy is substantial. Unlike many other cancers, curative metastasectomy is possible upon recurrence, which raises the question of personalized surveillance strategies according to individual risk factors. We studied whether elevated biomarkers, such as gold standard CEA and experimental CA19-9, IL-6, CRP, and YKL-40 after adjuvant therapy, are associated with disease-free and/or overall survival, and whether the diagnostic time from the elevated biomarker to the diagnosis of metastases can be prolonged by combining these biomarkers. We show that elevated post-adjuvant CEA, IL-6, and CRP are associated with impaired survival and that elevated IL-6 finds recurrences in patients with normal CEA. Lead time is shorter with CEA than with experimental biomarkers. Our findings thus may impact the follow-up strategies after curative intent treatment aiming at finding operable relapses. These biomarkers are readily available and feasible in clinical practice. In colorectal cancer (CRC), 20-50% of patients relapse after curative-intent surgery with or without adjuvant therapy. We investigated the lead times and prognostic value of post-adjuvant (8 months from randomisation to adjuvant treatment) serum CEA, CA19-9, IL-6, CRP, and YKL-40. We included 147 radically resected stage II-IV CRC treated with 24 weeks of adjuvant 5-fluorouracil-based chemotherapy in the phase III LIPSYT-study (ISRCTN98405441). All 147 were included in lead time analysis, but 12 relapsing during adjuvant therapy were excluded from post-adjuvant analysis. Elevated post-adjuvant CEA, IL-6, and CRP were associated with impaired disease-free survival (DFS) with hazard ratio (HR) 5.21 (95% confidence interval 2.32-11.69); 3.72 (1.99-6.95); 2.58 (1.18-5.61), respectively, and elevated IL-6 and CRP with impaired overall survival (OS) HR 3.06 (1.64-5.73); 3.41 (1.55-7.49), respectively. Elevated post-adjuvant IL-6 in CEA-normal patients identified a subgroup with impaired DFS. HR 3.12 (1.38-7.04) and OS, HR 3.20 (1.39-7.37). The lead times between the elevated biomarker and radiological relapse were 7.8 months for CEA and 10.0-53.1 months for CA19-9, IL-6, CRP, and YKL-40, and the lead time for the five combined was 27.3 months. Elevated post-adjuvant CEA, IL-6, and CRP were associated with impaired DFS. The lead time was shortest for CEA.
  • Niemelä, Markus; Niemelä, Onni; Bloigu, Risto; Bloigu, Aini; Kangastupa, Päivikki; Juvonen, Tatu (2020)
    Purpose: While extreme physical exertion is known to induce changes in the status of inflammation comparisons of the responses for various mediators of inflammation after acute bouts of high-intensity exercise have been limited. Subjects and Methods: We examined the responses in serum levels of novel inflammatory proteins, calprotectin, suPAR, CD163, and pro- and anti-inflammatory cytokines in 12 physically active volunteers (10 men, 2 women, mean age 37 +/- 14 years) before and after completing various types of extreme physical exertion (marathon run, half-marathon run or 24-h cross-country skiing). For comparisons, the levels of the biomarkers were also measured at rest in 30 healthy controls (25 men, 5 women, mean age 42 +/- 12 years) with low or sedentary activity. Results: Extreme physical exertion induced significant increases in serum calprotectin (p <0.0005), suPAR (p <0.01), CD163 (p <0.05), IL-6 (p <0.0005), IL-8 (p <0.01) and IL-10 (p <0.0005) (pre- vs 3h-post-exercise). These responses were found to normalize within 48 hours. While the increases in blood leukocytes were of similar magnitude following the different types of exercise, markedly more pronounced responses occurred in serum TNF-alpha (p <0.01), IL-8 (p <0.01) and CD163 (p <0.05) in those with more intense activity. In 3-h post-exercise samples significant correlations were observed between serum calprotectin and IL-6 (r(s) = 0.720, p <0.01), IL-10 (r(s) = 0.615, p <0.05), TNF-alpha (r(s) = 0.594, p <0.05), suPAR (r(s) = 0.587, p <0.05) and blood leukocytes (r(s) = 0.762, p <0.01). Conclusion: The present results suggest distinct exercise-intensity dependent changes in mediators of inflammation (including calprotectin, suPAR and CD163) following extreme physical exertion. Our findings indicate that there is a major reversible impact of high-intensity physical exertion on the status of inflammation.
  • Tietäväinen, Johanna; Mäkelä, Satu; Huhtala, Heini; Pörsti, Ilkka H; Strandin, Tomas; Vaheri, Antti; Mustonen, Jukka (2021)
    Puumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome characterized by thrombocytopenia, increased capillary leakage, and acute kidney injury (AKI). As glucosuria at hospital admission predicts the severity of PUUV infection, we explored how plasma glucose concentration associates with disease severity. Plasma glucose values were measured during hospital care in 185 patients with PUUV infection. They were divided into two groups according to maximum plasma glucose concentration: P-Gluc < 7.8 mmol/L (n = 134) and P-Gluc >= 7.8 mmol/L (n = 51). The determinants of disease severity were analyzed across groups. Patients with P-Gluc >= 7.8 mmol/L had higher hematocrit (0.46 vs. 0.43; p < 0.001) and lower plasma albumin concentration (24 vs. 29 g/L; p < 0.001) than patients with P-Gluc < 7.8 mmol/L. They presented with higher prevalence of pulmonary infiltrations and pleural effusion in chest radiograph, higher prevalence of shock and greater weight change during hospitalization. Patients with P-Gluc >= 7.8 mmol/L were characterized by lower platelet count (50 vs. 66 x 10(9)/L; p = 0.001), more severe AKI (plasma creatinine 272 vs. 151 mu mol/L; p = 0.001), and longer hospital treatment (8 vs. 6 days; p < 0.001) than patients with P-Gluc < 7.8 mmol/L. Plasma glucose level is associated with the severity of capillary leakage, thrombocytopenia, inflammation, and AKI in patients with acute PUUV infection.
  • Libraty, Daniel H.; Makela, Satu; Vlk, Jennifer; Hurme, Mikko; Vaheri, Antti; Ennis, Francis A.; Mustonen, Jukka (2012)