Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genes overexpressed in pancreatic islets of patients with new-onset type 1 diabetes are potential candidates for novel disease-related autoantigens. RT-PCR-based subtractive hybridization was used on islets from a patient who died at the onset of type 1 diabetes, and it identified a type 1 diabetes-related cDNA encoding hepatocarcinoma-intestine-pancreas/pancreatic-associated protein (HIP/PAP). This protein belongs to the family of Reg proteins implicated in islet regeneration; its gene contains a putative interleukin-6 (IL-6) response element. Islets from healthy cadaveric human donors released HIP/PAP protein into the culture medium, and this release was enhanced by the addition of IL-6. The expression pattern of mouse homologues of HIP/PAP was determined in pancreata of prediabetic and diabetic NOD mice. Both groups showed positive immunostaining for HIP/PAP in islets and ductal epithelium. To test whether HIP/PAP is a target of islet-directed autoimmunity, we measured splenic T-cell responses against HIP/PAP in NOD mice. Spontaneous proliferation was detected after 4 weeks. Lymphocytes from islet infiltrates and pancreatic lymph nodes from 7- to 10-week-old NOD mice were used to establish an HIP/PAP-specific I-A(g7)-restricted T-cell line, termed WY1, that also responded to mouse islets. WY1 cells homed to islets of NOD-SCID mice and adoptively transferred disease when coinjected with purified CD8(+) cells from diabetic NOD mice. Our conclusion was that differential cloning of Reg from islets of a type 1 diabetic patient and the response of Reg to the cytokine IL-6 suggests that HIP/PAP becomes overexpressed in human diabetic islets because of the local inflammatory response. HIP/PAP acts as a T-cell autoantigen in NOD mice. Therefore, autoimmunity to HIP/PAP might create a vicious cycle, accelerating the immune process leading to diabetes.
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PMID:A Reg family protein is overexpressed in islets from a patient with new-onset type 1 diabetes and acts as T-cell autoantigen in NOD mice. 1181 40

There is some evidence that major depression is accompanied by activation of the inflammatory response system (IRS). There is also evidence that proinflammatory cytokines and induction of IRS activation are associated with sickness behavior in experimental animals. However, no research has examined the IRS in somatization disorder. The aim of this study was to examine possible immunological differences between major depression, somatization and healthy controls. We measured the following IRS variables in patients with major depression (n=36), somatization syndrome (SSI-8; n=37), major depression and somatization (n=40) and healthy controls (n=37): interleukin-6 (IL-6); interleukin-1-receptor-antagonist (IL-1RA); plasma soluble interleukin-6 receptor (IL-6R); soluble suppressor/cytotoxic antigen (CD8); leukemia inhibitory factor (LIF-R); and Clara cell protein (CC16), an endogenous anticytokine. Serum CD8 concentrations were significantly increased in patients with major depression compared with concentrations in patients with somatization syndrome, whereas concentrations in normal controls were intermediate between those of the two groups of patients. Serum CC16 was significantly lower in major depression than in healthy controls. The highest CC16 scores were found in patients with somatization syndrome. Somatizing patients have significantly lower serum IL-6 values than normal controls and depressed patients. The present results indicate (1) an activation of the IRS in depression with signs of T-cell activation (increased CD8), monocytic activation (IL-1RA) and a lowered anti-inflammatory capacity of the serum (lower CC16) and (2) an immune alteration in somatizing syndrome, such as monocytic activation (increased IL-1RA) and indicators of lowered T-lymphocytic activity (lowered CD8 and IL-6). These results suggest different immune alterations in somatization syndrome and depression.
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PMID:Immunological differences between patients with major depression and somatization syndrome. 1181 36

BACKGROUND: In Japan, much attention has recently been paid to super-extended paraaortic lymphadenectomy (PAL) for the treatment of advanced gastric cancer. However, it has been reported that PAL is associated with increased morbidity and mortality, as compared to conventional extended lymphadenectomy (D2 or D3). Therefore, an analysis of the effects of PAL on perioperative changes in the biological responses of patients essential for determining the potential utility of this procedure.METHODS: The current non-randomized prospective study included evaluations of perioperative changes in parameters of surgical stress (series I; serum levels of antidiuretic hormone, interleukin-6, trypsin, and phospholipase A(2)) and immunocompetence (series II; phytohemagglutinin- and concanavalin A-induced blastogenesis, activity of natural killer cells and the ratio of CD4 cells to CD8 cells) in patients with advanced gastric cancer (T3 or T4), comparing groups treated with D3 plus PAL ( n = 12) and D3 ( n = 13), and a control group with early gastric cancer ( n = 16) treated with D1 lymphadenectomy (perigastric N1 nodes) between April 1995 and April 1997.RESULTS: The duration of surgery and the amount of blood lost were longer and greater in the D3 plus PAL group than in the D3 and D1 groups. D3 plus PAL and D3 were associated with significant postoperative increases in parameters of surgical stress, as well as with significant postoperative immunosuppression, compared to results with D1. However, there were no significant differences in the respective parameters between the D3 plus PAL and D3 groups.CONCLUSIONS: Our results indicate that there are no essential differences in patients' biological responses between D3 plus PAL and D3 lymphadenectomy. It appears that PAL-associated morbidity can be minimized by very careful manipulation during the dissection of paraaortic lymph nodes.
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PMID:Effects of super-extended paraaortic lymphadenectomy (PAL) on biological responses in totally gastrectomized patients with T3 or T4 gastric cancer. 1195 44

The pathogenesis of alcohol-related liver disease (ALD) remains inadequately explained. Increasing alcohol intake is associated with an increased risk of ALD, but many heavy drinkers develop no liver damage. An explanation for ALD susceptibility requires theories that extend beyond a biochemical understanding of alcohol metabolism. Several hepatic cell populations are involved in the pathogenesis of liver injury. The liver-associated lymphocyte (LAL) response to alcohol intake plus immune stimulation may determine susceptibility to liver damage. We have isolated rat LALs and demonstrated the following: (1) Liver-associated lymphocytes differ from the peripheral blood lymphocyte pool; the CD8:CD4 ratio is higher in the LAL population than in peripheral blood. (2) Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 production by these cells is suppressed by regular alcohol intake. (3) Tumor necrosis factor-alpha and interleukin-6 production by LALs is increased after parenteral administration of concanavalin A (Con A) and by Con A in in vitro LAL cultures obtained from healthy (control) and ethanol-consuming rats. (4) In vivo stimuli that lead to increased cytokine production by LALs lead, within 12-24 h, to increased hepatocyte necrosis [elevated alanine aminotransferase (ALT) levels] and apoptosis. (5) Liver-associated lymphocytes isolated from ethanol-consuming rats, transferred to non-ethanol-consuming rats, confer on the latter animals an ethanol-consuming response to Con A. (6) Cytokine release by LALs is quantitatively as significant as that from Kupffer cells after exposure to lipopolysaccharide. (7) In co-culture studies inhibition of TNF-alpha activity reduces hepatocyte apoptosis induced in the presence of activated LALs. (8) Finally, nuclear factor-kappa B inhibition decreases production of nitric oxide and TNF-alpha, with an associated reduction in hepatocyte apoptosis. In summary, our study findings support the suggestion that a role for LALs exists in the pathogenesis of alcohol and Con A-mediated liver disease.
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PMID:Lymphocyte-mediated liver injury in alcohol-related hepatitis. 1206 35

An empirically established chemoimmunotherapy for metastatic melanoma combines the systemic administration of the chemotherapeutic agent dacarbazine (DTIC) with the epifocal application of the contact sensitizer 2,4-dinitrochlorobenzene (DNCB) on cutaneous metastases. Although this therapy yields high response rates resulting in prolonged survival, the mechanisms involved remain unknown. Here, we investigated whether treatment of tumor-bearing mice with DTIC and DNCB resulted in a specific immune response against the tumor. Subcutaneous (s.c.) tumors and lung metastases were induced in C57BL/6 mice by injecting syngeneic B16-melanoma cells s.c. or into the lateral tail vein, respectively. Mice were treated with intraperitoneal injections of DTIC followed by epifocal application of DNCB. This therapeutic approach significantly reduced the growth of s.c. tumors as well as lung metastases. Our data showed that the effector mechanisms involved are dependent on T cells. No therapeutic effect was observed in immunodeficient RAG-1(-/-) mice, or when the contact sensitizer DNCB was replaced by skin irritants (croton oil or tributyltin). Splenic lymphocytes obtained from treated mice displayed a three-fold higher specific cytolytic activity against B16 cells than in tumor-bearing controls. Both CD8(+) and CD4(+) T cells were able to lyse B16 cells. No changes were observed in natural killer (NK) cell activity. Likewise, tumor-infiltrating lymphocytes (TIL) of treated mice showed higher cytolytic activity than that of controls. Analysis of cytokine expression in s.c. tumors revealed increased mRNA levels of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) in treated tumors. Together, these findings demonstrate the ability of DTIC/DNCB treatment to induce an effective T cell-dependent host immune response against a syngeneic tumor.
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PMID:Chemoimmunotherapy for melanoma with dacarbazine and 2,4-dinitrochlorobenzene elicits a specific T cell-dependent immune response. 1220 4

Kaposi's sarcoma (KS), the most common malignancy associated with HIV infection, is caused by the Kaposi sarcoma herpesvirus (KSHV). Exacerbations of KSHV are associated with increased human interleukin-6 (HuIL-6), and elevated IL-6 could be related to the development of KS. IL-4, a cytokine with pleiotropic effects, suppresses IL-6 in vivo and modestly inhibits AIDS-KS-derived cells in vitro. Suppression of IL-6 by exogenous IL-4 could result in antitumor activity. We report the results of a clinical trial to test this hypothesis. A phase I/II dose escalation safety, tolerance, and efficacy trial was conducted in patients with biopsy-proven AIDS-related KS, at two university medical centers. Patients were scheduled to receive IL-4 (0.5, 1.5, 3.0, or 4.0 microg/kg/day) administered subcutaneously (s.c.) in sequential cohorts. Patients were continued on study as long as the drug was tolerated or the disease progressed. Patients were followed for antitumor activity, effects on viral replication, immune status, and clinical and laboratory toxicity. Seventeen patients were enrolled at two sites over a 21-month period. There were 15 males and 2 females, and 1 patient was Hispanic. All patients had a Karnofsky score >70. Patients enrolled only into the two lower dose cohorts (0.5 and 1.5 microg/kg/day). Both groups had similar baseline characteristics. The median time on treatment was only 7.4 and 8.4 weeks for the 0.5 and 1.5 microg/kg/day dose levels, respectively. There was significant neutropenia, with 6 patients having grade 3 or greater toxicity requiring granulocyte colony-stimulating factor (G-CSF). Three patients on a dose of 1.5 microg/kg/day stopped treatment due to protocol-defined toxicity. There were no appreciable effects on CD4/CD8 counts. HIV viral RNA did not significantly change over time. However, in several people, it appeared to decline with treatment and rebound with discontinuation of treatment. Corresponding changes were noted in the HIV immunocomplex dissociated (ICD) p24 antigen. One patient had a partial response, 11 patients had stable disease, and 5 patients had disease progression during the short period of treatment. The maximum tolerated dose for IL-4 in patients with advanced AIDS-related KS is 1.5 microg/kg/day. At this dose level, IL-4 is poorly tolerated and is not an effective KS treatment. Treatment of the majority of patients is discontinued because of drug-related toxicity or because of disease progression. Future studies of IL-4 should be confined to studies of cytokine manipulation of the underlying HIV infection, as there appears to be little antitumor activity.
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PMID:Lack of antitumor activity and intolerance of interleukin-4 in patients with advanced HIV disease and Kaposi's sarcoma. 1251 14

We evaluated the role of interleukin-6 (IL-6) in neuronal injury after CNS infection. IL-6-/- and IL-6+/+ mice of resistant major histocompatibility complex (MHC) H-2b haplotype intracerebrally infected with Theiler's virus cleared the infection normally without development of viral persistence, lethal neuronal infection, or late phase demyelination. In contrast, infection of IL-6-/- mice on a susceptible H-2q haplotype resulted in frequent deaths and severe neurologic deficits within 2 weeks of infection as compared with infected IL-6+/+ H-2q littermate controls. Morphologic analysis demonstrated dramatic injury to anterior horn neurons of IL-6-/- H-2q mice at 12 d after infection. Infectious viral titers in the CNS (brain and spinal cord combined) were equivalent between IL-6-/- H-2q and IL-6+/+ H-2q mice. In contrast, more viral RNA was detected in the spinal cord of IL-6-/- mice compared with IL-6+/+ H-2q mice. Virus antigen was localized predominantly to anterior horn cells in infected IL-6-/- H-2q mice. IL-6 deletion did not affect the humoral response directed against virus, nor did it affect the expression of CD4, CD8, MHC class I, or MHC class II in the CNS. Importantly, IL-6 was expressed by astrocytes of infected IL-6+/+ mice but not in astrocytes of IL-6-/- mice or uninfected IL-6+/+ mice. Furthermore, expression of various chemokines was robust at 12 d after infection in both H-2b and H-2q IL-6-/- mice, indicating that intrinsic CNS inflammatory responses did not depend on the presence of IL-6. Finally, in vitro analysis of virus-induced death in neuroblastoma-spinal cord-34 motor neurons and primary anterior horn cell neurons showed that IL-6 exerted a neuroprotective effect. These data support the hypothesis that IL-6 plays a critical role in protecting specific populations of neurons from irreversible injury.
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PMID:Interleukin-6 protects anterior horn neurons from lethal virus-induced injury. 1253 8

A multiparametric analysis of immune components was performed in blood and serum of 61 voluntary persons before and after (1 day, 3 days, 4-6 months, 10-12 months) a professional pest control operation (PCO) using pyrethroids. Following parameters were included in the study (1) immunological parameters of the humoral defence, i.e. immunoglobulins of the classes A, G, M and E, complement components C3c and C4, acute phase proteins such as acid alpha 1-glycoprotein, haptoglobin, C-reactive protein; (2) mediators and receptors of immunity, i.e. neopterin, soluble interleukin-2 receptor (sIL-2R), soluble interleukin-6 receptor (sIL-6R), soluble tumor necrosis factor receptor (sTNF RII); (3) immunological markers of the cellular defence, i.e. white blood cell counts and lymphocyte (sub)populations such as total lymphocytes (CD2), mature lymphocytes (CD3), T-helper/inducer cells (CD4), T-suppressor/cytotoxic cells (CD8), B-cells (CD20), natural killer cells (CD56), as well as the ratio of CD4/CD8. The medians of all investigated immune components found before and for all time intervals after pyrethroid application were within the reference interval with respect to the total collective. Within this physiological range the investigated parameters showed a trend to lower values predominantly during the early phase (1 and 3 days) after PCO, partially being significant. Significant decreases were no more present in the late phase (6 to 12 month) after PCO indicating reversibility. Atopics did not differ in the immune response after PCO as compared to non-atopics. Obtained results suggest a modulation of immune components after a correct performed PCO within the physiological range towards lower values during the first days. However these immune changes are considered to be subtle and underlying compensatory mechanisms of immunoregulation.
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PMID:Pyrethroids used indoors--immune status of humans exposed to pyrethroids following a pest control operation--a one year follow-up study. 1270 30

We have determined the percentage of alphabeta and gammadelta T cells by flow cytometry as well as serum interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R) levels by enzyme-linked immunosorbent assay in kidney allograft recipients with acute, chronic or stable graft evolution. The percentage of CD4 and CD8 T cells in transplanted patients was lower than in the control group (P < 0.001) with the exception of CD8 gammadelta T cells from patients with stable evolution (P > 0.05). The serum levels of IL-6 and sIL-6R in acute and chronic rejection were higher than in the controls (P < 0.05). No differences in IL-6 levels were observed between the stable evolution and the control groups (P > 0.05). The levels of sIL-6R were higher in stable evolution patients than in the controls (P < 0.05) and no differences were observed between the chronic and stable evolution patients (P > 0.05). IL-6 decreased in patients with a favourable evolution, increased in those with an increased renal dysfunction and was maintained when the renal dysfunction was not modified. These results suggest that gammadelta T cells could participate in renal allograft maintenance and that IL-6 but not sIL-6R serum levels may provide a prognostic marker for measuring the evolution of kidney allograft.
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PMID:Gammadelta T cells and interleukin-6 levels could provide information regarding the progression of human renal allograft. 1282 64

Inflammation has been reported to play an important role in cardiac surgery under cardiopulmonary bypass due to systemic endotoxemia. In order to develop strategies against this injury in future we studied the combined effect of a number of inflammatory mediators in myocardial ischemia/reperfusion. Coronary sinus blood samples of ten patients undergoing coronary artery bypass graft surgery (CABG) were obtained at three time intervals (1) before onset of bypass (2) 30 min after cross clamp, and (3) 10 min after removal of cross clamp. The samples were subjected to evaluate levels of nitric oxide byproducts (nitrite and nitrate and citrulline), inflammatory cytokines (interleukin-2, interferon-gamma and interleukin-6), adhesion molecules, (CD62L and CD54), ratio of cell surface markers (CD4/CD8 and TCRalphabeta/gammadelta) cell activation markers (CD69 and HLA DR) and second messengers (protein kinase C, inositol 1,4,5 triphosphate and intracellular calcium levels). Ischemia and further reperfusion resulted in significant rise in nitrite and nitrate levels (p < 0.001), interleukin-6 (p < 0.01), CD62L (p < 0.001), CD69 (p < 0.05), protein kinase C (p < 0.001) and intracellular calcium (p < 0.001). A fall in CD4/CD8 ratio was observed on reperfusion. These changes during CABG show that ischemia/reperfusion leads to a release of an array of pro-inflammatory mediators of tissue injury, which could lead to pathophysiological changes. Hence the study suggests the need of some protective therapies against these inflammatory markers.
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PMID:Release of pro-inflammatory mediators during myocardial ischemia/reperfusion in coronary artery bypass graft surgery. 1284 27


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