Circulating concentrations of interleukin-6 in cancer patients and their pathogenic role in tumor-induced hypercalcemia

Circulating interleukin-6 (IL-6) concentrations correlate with disease activity in severe inflammatory conditions, in sepsis and in some hematological malignancies. On the other hand, IL-6 is a potent stimulator of osteoclastogenesis and has been implicated as a contributory factor in the genesis of osteopenic conditions. We measured circulating IL-6 levels by a sensitive (detection limit of 10 U/ml) and specific bioassay in 103 patients with advanced cancer, including 41 with tumor-induced hypercalcemia before any specific hypocalcemic therapy. We related IL-6 concentrations to clinical features and to biochemical parameters of bone metabolism, including blood Ca, Ca²⁺, P_i, intact parathyroid hormone, parathyroid hormone-related protein, osteocalcin, 1,25-(OH)₂-vitamin D and, as markers of bone resorption, the fasting urinary excretion of calcium (Ca/creatinine) and hydroxyproline. IL-6 levels were increased, i.e. detectable, in 23% of the patients, 8/41 (20%) hypercalcemic and 16/62 (26%) normocalcemic patients (NS); the distribution of the values was similar in the two groups. The presence of increased IL-6 concentrations was not related to any clinical characteristic, notably not to the survival nor to the existence of bone metastases, whether in hypercalcemic or normocalcemic patients; e.g., only 3/12 (25%) hypercalcemic subjects without bone metastases had elevated IL-6 levels. We found no significant correlations between IL-6 concentrations and any of the biochemical parameters studied. Hypercalcemic subjects with increased IL-6 had higher urinary Ca/creatinine levels than patients with normal IL-6 levels (P<0.005) but this was not the case in normocalcemic subjects. Mean concentrations of inflammatory or other bone metabolism markers were not significantly different between patients with normal or with elevated IL-6 levels. In summary, circulating IL-6 levels were increased in 23% of 103 patients with advanced cancer, but the frequency of increased IL-6 concentrations was not related to the presence of hypercalcemia or to any marker of calcium metabolism or bone turnover. The pathogenic importance of circulating IL-6 in patients with solid tumors remains to be demonstrated and our data indicate that increased circulating levels of IL-6, possibly reflecting the activation of the immune system, only contribute in a minor way to the osteolytic process in patients with tumor-induced hypercalcemia.     

Associations of interleukin-6 with interleukin-1beta, interleukin-8 and macrophage inflammatory protein-1beta in midlife women

Objective: The aim of the present study was to determine the associations of interleukin (IL)-6 with other cytokines and chemokines and to compare these associations in peri- and postmenopausal women. Methods: Ninety-nine perimenopausal and 92 postmenopausal women were enrolled in this study. Serum concentrations of IL-6, IL-1β, IL-2, IL-4, IL-5, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, tumor necrosis factor (TNF)-α, interferon γ, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage (GM)-CSF, macrophage inflammatory protein (MIP)-1β and monocyte chemotactic protein (MCP)-1 were measured simultaneously using a multiplexed cytokine assay. Results: Among the 17 cytokines, IL-6, IL-1β, IL-5, IL-7, IL-8, IL-10, MCP-1 and MIP-1β were detected in serum in more than 50% of the women. Serum levels of IL-4 and MCP-1 in postmenopausal women were significantly higher than those in perimenopausal women. Serum IL-6 concentrations showed significant and positive correlations with serum concentrations of IL-1β, IL-8, MIP-1β, IL-7 and MCP-1 in women regardless of menopausal status, and these correlations were still significant after adjustment for age and body mass index. Conclusion: Serum IL-6 concentration was found to be closely associated with serum concentrations of IL-1β, IL-8, MIP-1β, IL-7 and MCP-1 in women regardless of menopausal status, suggesting that these cytokines act in concert with the progression of several symptoms and various diseases.     

Molecular Characterisation of Chikungunya Virus Infections in Trinidad and Comparison of Clinical and Laboratory Features with Dengue and Other Acute Febrile Cases

Local transmission of Chikungunya virus (CHIKV) was first documented in Trinidad and Tobago (T&T) in July 2014 preceding a large epidemic. At initial presentation, it is difficult to distinguish chikungunya fever (CHIKF) from other acute undifferentiated febrile illnesses (AUFIs), including life-threatening dengue disease. We characterised and compared dengue virus (DENV) and CHIKV infections in 158 patients presenting with suspected dengue fever (DF) and CHIKF at a major hospital in T&T, and performed phylogenetic analyses on CHIKV genomic sequences recovered from 8 individuals. The characteristics of patients with and without PCR-confirmed CHIKV were compared using Pearson’s χ² and student’s t-tests, and adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were determined using logistic regression. We then compared signs and symptoms of people with RT-qPCR-confirmed CHIKV and DENV infections using the Mann-Whitney U, Pearson’s χ² and Fisher’s exact tests. Among the 158 persons there were 8 (6%) RT-qPCR-confirmed DENV and 30 (22%) RT-qPCR-confirmed CHIKV infections. Phylogenetic analyses showed that the CHIKV strains belonged to the Asian genotype and were most closely related to a British Virgin Islands strain isolated at the beginning of the 2013/14 outbreak in the Americas. Compared to persons who were RT-qPCR-negative for CHIKV, RT-qPCR-positive individuals were significantly more likely to have joint pain (aOR: 4.52 [95% CI: 1.28–16.00]), less likely to be interviewed at a later stage of illness (days post onset of fever—aOR: 0.56 [0.40–0.78]) and had a lower white blood cell count (aOR: 0.83 [0.71–0.96]). Among the 38 patients with RT-qPCR-confirmed CHIKV or DENV, there were no significant differences in symptomatic presentation. However when individuals with serological evidence of recent DENV or CHIKV infection were included in the analyses, there were key differences in clinical presentation between CHIKF and other AUFIs including DF, which can be used to triage patients for appropriate care in the clinical setting.     

Serum and urine levels of interleukin-6 and interleukin-8 in children with acute pyelonephritis

Urinary tract infection (UTI) is a common clinical disorder in younger infants and children and may result in permanent renal damage. The inflammatory cytokines interleukin (IL)-6 and IL-8 play an important role in response to bacterial infection. This prospective study investigated the association between serum and urine IL-6 and IL-8 levels and acute pyelonephritis confirmed by (99m)Tc-dimercaptosuccinic acid (DMSA) scan. A total of 78 children aged 1-121 months with a diagnosis of first-time febrile UTI were included. The following inflammatory markers were assessed: fever; white blood cells count (WBC); C-reactive protein (CRP); and serum and urine IL-6 and IL-8. The patients were divided into the acute pyelonephritis group (n=42) and the lower UTI group (n=36) according to the results of DMSA scan. Fever, WBC and CRP levels were significantly higher in children with acute pyelonephritis than in those with lower UTI (all p <0.001). Significantly, higher initial serum and urine IL-6 and IL-8 levels were found in children with acute pyelonephritis than in those with lower UTI (all p <0.001). Serum and urine IL-6 in children with acute pyelonephritis were positively correlated with fever, CRP and leucocyturia. These results indicate that both serum and urine IL-6 and IL-8 levels, particularly IL-6, are useful diagnostic tools for early recognition of acute pyelonephritis in febrile children.     

The interleukin-6 G(-174)C polymorphism and the ex vivo interleukin-6 response to endotoxin in severely injured blunt trauma patients

The aim of this study was to evaluate whether the -174 G/C promoter polymorphism of the interleukin-6 (IL-6) gene is associated with the ex vivo, whole blood IL-6 response to endotoxin with the development of severe sepsis in severely injured, blunt trauma patients. Patients with a severe trauma and an injury severity score of 16 were included in the study. The IL-6 -174 G/C promoter polymorphism was determined by real-time polymerase chain reaction (PCR) assay using specific fluorescence-labelled hybridisation probes. Whole blood of the patients was stimulated with endotoxin and the IL-6 concentrations were measured by ELISA. There was no association between the IL-6 -174 genotypes and the ex vivo, stimulated IL-6 response: 25% of the patients developed severe sepsis later in the clinical course. These patients had higher IL-6 concentrations following whole blood stimulation on day 1 (p = 0.046) after the trauma than patients with uncomplicated post-traumatic recovery. The difference was even more significant on day 2 after the trauma (p = 0.02). High IL-6 responses in a whole blood stimulation assay with endotoxin on days 1 and 2 after a trauma are associated with severe post-traumatic sepsis. Genotyping for the IL-6 -174 G/C polymorphism does not allow early identification of trauma patients with a high, ex vivo IL-6 synthesis capacity.     

Role of interleukin-12 in patients with dengue hemorrhagic fever

Interleukin (IL)-12 has a broad range of activities including regulation of cytokine synthesis and selective promotion of Th1-type cell development. A shift from a Th1-type response to Th2-type has been suggested to be important in the pathogenesis of dengue hemorrhagic fever (DHF). This study was undertaken to investigate the possible role of IL-12 in this shift. A total of 76 patients with various grades of dengue illness and 21 normal healthy controls were tested for IL-12 levels in serum samples and IL-12 mRNA in their peripheral blood mononuclear cells. The results showed that the levels of IL-12 were the highest in patients with dengue fever (270+/-102 pg ml(-1)) followed by decreasing levels in the patients with DHF grade I (198+/-86 pg ml(-1); P<0.05) and DHF grade II (84+/-52 pg ml(-1); P<0.001). Neither IL-12 nor its mRNA could be detected in the patients with DHF grades III and IV. The cytokine appeared and reached peak levels during the first 4 days of illness, started to decline by day 5-8 and disappeared by day 9 onwards. The absence of IL-12 during severe illness and late phases of the disease may be responsible for the shift to a Th2-type response and thus for the pathogenesis of DHF.     

Profile of circulating levels of IL-1Ra, CXCL10/IP-10, CCL4/MIP-1β and CCL2/MCP-1 in dengue fever and parvovirosis

Dengue virus (DENV) and parvovirus B19 (B19V) infections are acute exanthematic febrile illnesses that are not easily differentiated on clinical grounds and affect the paediatric population. Patients with these acute exanthematic diseases were studied. Fever was more frequent in DENV than in B19V-infected patients. Arthritis/arthralgias with DENV infection were shown to be significantly more frequent in adults than in children. The circulating levels of interleukin (IL)-1 receptor antagonist (Ra), CXCL10/inducible protein-10 (IP-10), CCL4/macrophage inflammatory protein-1 beta and CCL2/monocyte chemotactic protein-1 (MCP-1) were determined by multiplex immunoassay in serum samples obtained from B19V (37) and DENV-infected (36) patients and from healthy individuals (7). Forward stepwise logistic regression analysis revealed that circulating CXCL10/IP-10 tends to be associated with DENV infection and that IL-1Ra was significantly associated with DENV infection. Similar analysis showed that circulating CCL2/MCP-1 tends to be associated with B19V infection. In dengue fever, increased circulating IL-1Ra may exert antipyretic actions in an effort to counteract the already increased concentrations of IL-1β, while CXCL10/IP-10 was confirmed as a strong pro-inflammatory marker. Recruitment of monocytes/macrophages and upregulation of the humoral immune response by CCL2/MCP-1 by B19V may be involved in the persistence of the infection. Children with B19V or DENV infections had levels of these cytokines similar to those of adult patients.     

Epoxyisoprostane and epoxycyclopentenone phospholipids regulate monocyte chemotactic protein-1 and interleukin-8 synthesis. Formation of these oxidized phospholipids in response to interleukin-1beta.

Monocyte recruitment to the vessel wall, mediated by monocyte chemotactic protein-1 (MCP-1) and interleukin-8 (IL-8), plays an important role in atherogenesis. We have shown previously that minimally oxidized low density lipoprotein, oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (Ox-PAPC), activates endothelial cells to produce MCP-1 and IL-8. By using liquid chromatography/mass spectrometry methods coupled with bioassay, we report a family of epoxyisoprostane (PEIPC) and epoxycyclopentenone (PECPC) phospholipids that are the components of Ox-PAPC responsible for the majority of this activity. Ox-PAPC contains five chromatographically distinguishable active PEIPC components (m/z 825.5) and four PECPC components (m/z 810.5). All nine components induced endothelial cell synthesis of IL-8 and MCP-1 in a dose-dependent fashion between 0.1 and 5 microm concentrations. The five PEIPC components had identical functional groups and all underwent dehydration to produce m/z 810.5. We present evidence that these phospholipids are regioisomers with epoxide groups at the 5,6-, 8,9-, 11,12-, or 14,15-positions of the sn-2 fatty acid and their epoxide groups is important for biological activity. We have shown previously that peroxisome proliferator-activated receptor alpha is involved in MCP-1 synthesis in response to Ox-PAPC. We now show that PEIPC and PECPC isomers are potent activators of peroxisome proliferator-activated receptor alpha. PEIPC and PECPC isomers are strongly recognized by specific circulating murine natural autoantibodies (EO6) and accumulate in cells treated with IL-1beta. These studies demonstrate that PEIPC and PECPC isomers are potent activators of endothelial cells increasing synthesis of IL-8 and MCP-1. Their accumulation in cells exposed to cytokines and in atherosclerotic lesions suggests that these lipids may play a role in a number of chronic disease processes.     

Age-related limitations of interleukin-6 in predicting early mortality in acute ST-elevation myocardial infarction

Interleukin-6 (IL-6) is an inflammatory cytokine whose levels increase significantly during myocardial infarction (MI).It has been hypothesised that the concentrations of IL-6 at admission may be useful in prognosticating long-term outcomes. It is unclear, however, whether IL-6 could improve the prognosis of early mortality in MI.We have compared serum IL-6 levels and analysed the disease course in 158 patients with ST-elevation MI (STEMI) who either survived (n?=?148) or died (n?=?10) within 30 days following the admission. Patients were treated in a single university centre with primary percutaneous coronary intervention (PCI).The non-survivors (6.3%) displayed most of typical risk factors for poor outcome. In addition they had significantly higher concentrations of IL-6 at hospital admission (median values 8.5 vs. 2.0 pg/ml; p?=?0.038). However, they were also significantly older than the survivors (median values 72 vs. 57 years; p?=?0.0001). IL-6 levels are known to increase with age and we could confirm a significant correlation between patients’ calendar age and circulating IL-6 (p?=?0.009). Regression analysis revealed that IL-6 concentrations were significantly affected by patients’ age but they did not independently relate to patients’ outcome.Such results indicate that circulating IL-6 at admission may be of limited value in predicting early mortality in STEMI. It is important to recognize that, because of the small group of patients who died (N?=?10), the results must be interpreted with caution. Therefore, we stress that these results should be viewed as preliminary and further validated in a larger set of patients.     

Study of 27 Aqueous Humor Cytokines in Type 2 Diabetic Patients with or without Macular Edema

The aim of the present study was to compare the changes in the levels of 27 aqueous humor cytokines between diabetic patients with macular edema (ME) and diabetic patients without ME. Undiluted aqueous humor samples were obtained from 68 consecutive type 2 diabetic patients without ME and 56 consecutive type 2 diabetic patients with ME. The concentrations of 27 cytokines in the aqueous humor samples were measured using a multiplex bead immunoassay. Compared with diabetic patients without ME, diabetic patients with ME had significantly higher concentrations of IL-1β, IL-6, IL-8, IP-10, MCP-1, and VEGF in the aqueous humor. However, the concentrations of IL-10 and IL-12 were significantly lower in the diabetic patients with ME. The aqueous humor levels of IL-1β, IL-6, IL-8, MCP-1, IP-10, and VEGF were closely correlated with retinal macular thickness, retinal macular volume and the severity of ME. In addition, the aqueous humor levels of IL-10 and IL-12 decreased with increasing the severity of ME. A variety of cytokines associated with inflammation and angiogenesis may contribute to the pathogenesis of diabetic macular edema, and both anti-inflammatory and antiangiogenic agents should be included in the treatment of ME simultaneously.     

Tumour necrosis factor-alpha (TNFalpha) and interleukin-10 are crucial mediators in post-operative systemic inflammatory response and determine the occurrence of complications after major abdominal surgery

BACKGROUND: The course of serum cytokine levels in patients with postoperative systemic inflammatory response syndrome (SIRS) after major abdominal surgery remains currently unclear. METHODS: Blood was sampled pre- and post-operatively and on days 1 and 2 in 40 patients undergoing major abdominal surgery. Concentrations of tumour necrosis factor-alpha (TNFalpha), interleukin (IL) -6, IL-8, and IL-10 were measured by the LINCOplex assay; those of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) by an enzyme immunoassay. RESULTS: Compared to their pre-operative values, sTREM-1 was elevated on day 2; TNFalpha on day 1; IL-6 and IL-10 post-operatively and on days 1 and 2; and IL-8 post-operatively and on day 1. The duration of operation correlated with TNFalpha and IL-10 at all sampling times, and with IL-6 post-operatively. There were no differences in cytokine concentrations between patients who exhibited post-operative complications and those who did not. IL-10/TNFalpha below 30 was found in all patients with complications (100%) and in 20 patients without complications (64.5%, p: 0.043). CONCLUSIONS: SIRS following major surgery is characterised by complex alterations in cytokine concentrations. The balance between TNFalpha and IL-10 seems to determine the occurrence of post-operative complications.     

Effect of berberrubine on interleukin-8 and monocyte chemotactic protein-1 expression in human retinal pigment epithelial cell line

We examined the effects of berberrubine, a protoberberine alkaloid, on interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) expression in a human retinal pigment epithelial cell line (ARPE-19) stimulated with interleukin-1beta (IL-1beta) or tumor necrosis factor alpha (TNF-alpha). ARPE-19 cells were cultured to confluence. Berberrubine and IL-1beta or TNF-alpha were added to the medium. IL-8 and MCP-1 protein concentrations were measured using enzyme-linked immunosorbent assay. IL-8 and MCP-1 mRNA were measured by real time polymerase chain reaction. Nuclear factor kappaB (NF-kappaB) translocation was examined by immunofluorescent staining/microscopy. Berberrubine dose-dependently inhibited IL-8 and MCP-1 protein levels in the media and mRNA expression of the cells stimulated with IL-1beta or TNF-alpha. Immunofluorescent staining/microscopy of NF-kappaB in the nucleus of unstimulated cells was faint (51+/-14 arbitrary units). Fluorescein was dense (215+/-42 or 170+/-24 arbitrary units, respectively) 30 min after stimulation with IL-1beta or TNF-alpha and was decreased to 62+/-18 or 47+/-16 arbitrary units, respectively, by berberrubine. Berberrubine dose-dependently inhibited IL-8 and MCP-1 expression and protein secretion induced by IL-1beta or TNF-alpha. Possibly, the effect on chemotactic factors may be via suppression of NF-kappaB translocation.     

Relationship of thrombopoietin and interleukin-11 levels to thrombocytopenia associated with dengue disease

Thrombocytopenia is one of the main clinical findings of dengue. In this work we examined the levels of thrombopoietin (TPO) and interleukin-11 (IL-11), two of the most potent regulators of platelet production, in serum from 28 patients with dengue fever (DF). Patients with DF had increased levels of TPO, compared with healthy individuals (p<0.005). Patients with dengue hemorrhagic fever (DHF, n=7), the more severe form of dengue, had higher TPO levels than patients with DF (p<0.001). Serum TPO levels and platelet counts were inversely correlated in both DF and DHF patients. IL-11 was detectable in neither DF nor DHF patients. Our results demonstrate that thrombocytopenia in dengue disease is associated with changes in the serum levels of TPO, but not IL-11, suggesting that this cytokine could be a potential early clinical marker of the severity of dengue disease.     

Relationship between serum concentrations of interleukin-6 and tumor necrosis factor alpha in female Turkish subjects with normal and impaired glucose tolerance.

Serum interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFalpha) concentrations were measured in subjects during two-hour glucose loading in order to investigate the effects of glucose on serum IL-6 and TNFalpha concentrations. Twenty-six female subjects (mean age 60 +/- 10 years) had normal glucose tolerance (NGT) and nineteen female subjects (mean age: 63 +/- 9 years) had impaired glucose tolerance (IGT) according to WHO criteria. Serum IL-6 and TNFalpha concentrations were measured by chemiluminescent immunometric assay. Subjects with IGT have higher fasting serum TNFalpha levels than subjects with NGT (p < 0.01). Serum IL-6 and TNFalpha concentrations were elevated during glucose loading (for each comparison, p < 0.01). The increase in serum TNFalpha concentrations in IGT was greater than in NGT (p < 0.01). Serum IL-6 and TNFalpha concentration significantly correlated with insulin and glucose in IGT group (for each comparison, p < 0.01). The correlation between serum glucose and cytokines concentrations was significant in IGT (for each comparison, p < 0.01). There was also a positive correlation between serum IL-6 and TNFalpha in NGT and IGT (for each comparison, p < 0.01). In conclusion, hyperglycemia is associated with increased circulating cytokine concentrations and fasting TNFalpha concentrations seem to be more associated with IGT than IL-6.     

Key role of regulated upon activation normal T-cell expressed and secreted, nonstructural protein1 and myeloperoxidase in cytokine storm induced by influenza virus PR-8 (A/H1N1) infection in A549 bronchial epithelial cells

Influenza virus infection causes severe respiratory disease such as that due to avian influenza (H5N1). Influenza A viruses proliferate in human epithelial cells, which produce inflammatory cytokines/chemokines as a "cytokine storm" attenuated with the viral nonstructural protein 1 (NS1). Cytokine/chemokine production in A549 epithelial cells infected with influenza A/H1N1 virus (PR-8) or nonstructural protein 1 (NS1) plasmid was examined in vitro. Because tumor necrosis factor-α (TNF-α) and regulated upon activation normal T-cell expressed and secreted (RANTES) are predominantly produced from cells infected with PR-8 virus, the effects of mRNA knockdown of these cytokines were investigated. Small interfering (si)TNF-α down-regulated RANTES expression and secretion of RANTES, interleukin (IL)-8, and monocyte chemotactic protein-1 (MCP-1). In addition, siRANTES suppressed interferon (IFN)-γ expression and secretion of RANTES, IL-8, and MCP-1, suggesting that TNF-α stimulates production of RANTES, IL-8, MCP-1, and IFN-γ, and RANTES also increased IL-8, MCP-1, and IFN-γ. Furthermore, administration of TNF-α promoted increased secretion of RANTES, IL-8, and MCP-1. Administration of RANTES enhanced IL-6, IL-8, and MCP-1 production without PR-8 infection. These results strongly suggest that, as an initial step, TNF-α regulates RANTES production, followed by increase of IL-6, IL-8, and MCP-1 and IFNs concentrations. At a later stage, cells transfected with viral NS1 plasmid showed production of a large amount of IL-8 and MCP-1 in the presence of the H(2)O(2)-myeloperoxidse (MPO) system, suggesting that NS1 of PR-8 may induce a "cytokine storm" from epithelial cells in the presence of an H(2)O(2)-MPO system.     

White adipose tissue production and release of IL-6 and TNF-alpha do not parallel circulating and cerebrospinal fluid concentrations in pregnant rats.

IL-6 and TNF-alpha are synthesized in white adipose tissue both by adipocytes and by the stroma-vascular fraction. They both are known to interfere with insulin signaling, reducing insulin sensitivity and lipid deposition. At a central level, IL-6 enhances sympathetic nervous system activity, thus enhancing lipolysis and reducing fat mass. During late pregnancy, white adipose tissue (WAT) mass increases and insulin sensitivity decreases. To assess the involvement of both adipokines in such processes, we analyzed the tissue content and release of both adipokines in parametrial and subcutaneous WAT depots and their circulating and cerebrospinal fluid concentrations in nonpregnant rats and in pregnant rats by days 8, 15, and 19 of pregnancy. The tissue content of both adipokines was enhanced 5-6 times by day 8 until the end of pregnancy in parametrial WAT, whereas the increase took place by day 15-19 in subcutaneous WAT. No increase in tissue release was detected, suggesting a local action. However, circulating IL-6 concentration was enhanced by day 8 until the end of pregnancy, suggesting sources other than WAT. IL-6 concentration in cerebrospinal fluid paralleled the increases in serum by days 8 and 15, suggesting a systemic origin. However, it returned to basal levels by day 19, suggesting a central control for IL-6 entrance. TNF-alpha was not detected in either serum or cerebrospinal fluid. These results led us to conclude that across pregnancy adipokines control WAT depots in a time- and depot-dependent manner. They do so directly, by local production, but the enhanced concentrations of both circulating and CSF IL-6 suggest an indirect action mediated by the nervous system.     

Macrophage-colony stimulating factor and interleukin-34 induce chemokines in human whole blood

The aim of this study is to investigate if macrophage-colony stimulating factor (M-CSF) or interleukin-34 (IL-34) induces cytokines or chemokines using human whole blood (HWB) and if an M-CSF- or IL-34-induced cytokine or chemokine production from HWB is inhibited by soluble M-CSF receptor or c-FMS kinase inhibitors. Among eight cytokines or growth factors tested, only IL-6 level was increased by up to 6-fold by M-CSF or IL-34 in HWB. In contrast, chemokine levels (IP-10/CXCL10, IL-8/CXCL8, and MCP-1/CCL2) were dramatically increased by M-CSF or IL-34 in HWB while exhibiting a large variation among donors. Variability of the MCP-1 signal induced by M-CSF or IL-34 was relatively less among donors compared to the IP-10 and IL-8 signals. The elevation of these chemokine levels was significantly decreased by soluble M-CSF receptor, indicating the elevation of these chemokines was mediated by M-CSF or IL-34. Furthermore, GW2580, a c-FMS kinase inhibitor, inhibited the induction of MCP-1 by M-CSF or IL-34 in a concentration dependent manner. These indicate MCP-1 is the most appropriate chemokine target for a chemokine release assay to evaluate the potency of c-FMS kinase inhibitors and MCP-1 release assay using HWB would be useful, relevant tool for translational pharmacology of c-FMS kinase inhibitors.     

Climate teleconnections and recent patterns of human and animal disease outbreaks

Background

Recent clusters of outbreaks of mosquito-borne diseases (Rift Valley fever and chikungunya) in Africa and parts of the Indian Ocean islands illustrate how interannual climate variability influences the changing risk patterns of disease outbreaks. Although Rift Valley fever outbreaks have been known to follow periods of above-normal rainfall, the timing of the outbreak events has largely been unknown. Similarly, there is inadequate knowledge on climate drivers of chikungunya outbreaks. We analyze a variety of climate and satellite-derived vegetation measurements to explain the coupling between patterns of climate variability and disease outbreaks of Rift Valley fever and chikungunya.

Methods and Findings

We derived a teleconnections map by correlating long-term monthly global precipitation data with the NINO3.4 sea surface temperature (SST) anomaly index. This map identifies regional hot-spots where rainfall variability may have an influence on the ecology of vector borne disease. Among the regions are Eastern and Southern Africa where outbreaks of chikungunya and Rift Valley fever occurred 2004–2009. Chikungunya and Rift Valley fever case locations were mapped to corresponding climate data anomalies to understand associations between specific anomaly patterns in ecological and climate variables and disease outbreak patterns through space and time. From these maps we explored associations among Rift Valley fever disease occurrence locations and cumulative rainfall and vegetation index anomalies. We illustrated the time lag between the driving climate conditions and the timing of the first case of Rift Valley fever. Results showed that reported outbreaks of Rift Valley fever occurred after ∼3–4 months of sustained above-normal rainfall and associated green-up in vegetation, conditions ideal for Rift Valley fever mosquito vectors. For chikungunya we explored associations among surface air temperature, precipitation anomalies, and chikungunya outbreak locations. We found that chikungunya outbreaks occurred under conditions of anomalously high temperatures and drought over Eastern Africa. However, in Southeast Asia, chikungunya outbreaks were negatively correlated (p<0.05) with drought conditions, but positively correlated with warmer-than-normal temperatures and rainfall.

Conclusions/Significance

Extremes in climate conditions forced by the El Niño/Southern Oscillation (ENSO) lead to severe droughts or floods, ideal ecological conditions for disease vectors to emerge, and may result in epizootics and epidemics of Rift Valley fever and chikungunya. However, the immune status of livestock (Rift Valley fever) and human (chikungunya) populations is a factor that is largely unknown but very likely plays a role in the spatial-temporal patterns of these disease outbreaks. As the frequency and severity of extremes in climate increase, the potential for globalization of vectors and disease is likely to accelerate. Understanding the underlying patterns of global and regional climate variability and their impacts on ecological drivers of vector-borne diseases is critical in long-range planning of appropriate disease and disease-vector response, control, and mitigation strategies.