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At least 19 recordsLinked to original sources
PubMed2003

Differential chemokine, chemokine receptor, cytokine and cytokine receptor expression in pulmonary adenocarcinoma: diffuse down-regulation is associated with immune evasion and brain metastasis.

Pulmonary adenocarcinoma is frequently associated with brain metastasis at some stage during the disease course. Host immunity, particularly T cell immunity, plays an important role in the clinicopathological features of carcinoma proliferation and metastasis. Cytokines and chemokines are members of a family of small secreted proteins. The relationships between the cytokines and cytokine receptor (R), and between chemokines and chemokine R are important determinants of selectivity in local immunity. RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) and Fas ligand (FasL) are present in neoplastic cells, induce apoptosis of NK/T cells, and play a role in immune evasion. To investigate differences in host immunity between pulmonary adenocarcinoma with and without brain metastasis, we performed gene expression profiling, using chemokine, chemokine R, cytokine and cytokine R DNA chips. In addition, to assess the extent of immune evasion, we examined the expression of RCAS and FasL. We studied five cases of pulmonary adenocarcinoma with brain metastasis (meta) and five cases without brain metastasis (non-meta). The brain meta cases exhibited diffuse down-regulated profiles, in comparison with normal non-carcinomatous lungs, which were used as controls. Non-meta cases also displayed diffuse down-regulation, however the degree was variable. Expression of RCAS and FasL was detected in almost all cases, but was stronger in meta than non-meta cases. Our findings suggested that tumor cells evaded host immunity. In the gene tree analysis, brain meta cases and non-meta cases exhibited distinct clustering. Brain meta cases exhibited significantly lower expression of interleukin 13 receptor alpha2 (IL-13Ralpha2) than non-meta cases. The reduction of IL-13Ralpha2 expression was confirmed by RT-PCR. Immunohistochemically, non-meta adenocarcinoma cells frequently expressed IL-13Ralpha2, however, IL-13Ralpha2 expression was rare or weak in adenocarcinomas with meta. Our results suggested that, in addition to immune evasion, the characteristics of the adenocarcinoma tumors themselves were important for brain metastasis. However, our study demonstrated the enormous potential of gene expression profiling in clarifying the pathogenesis of brain metastasis in pulmonary adenocarcinoma.

Adenocarcinoma↗
PubMed2004

Differential expression of chemokines, chemokine receptors, cytokines and cytokine receptors in diffuse large B cell malignant lymphoma.

Host immunity, particularly T cell immunity (Th1/Th2 balance), plays an important role in clinicopathological features of malignant disease. However, the T cell immunity has not been fully investigated in patients with lymphoid malignancies. Recent studies suggested the important role of dysregulation of the endogenous immune system in lymphomagenesis. The relationships between cytokines/chemokines and their receptors, are important in determining the selectivity of local immunity. To investigate differences in the endogenous immune system of diffuse large B cell lymphoma (DLBL), we performed gene expression profiling using cDNA microarrays of cytokines/chemokines and their receptors. We studied 5 cases each of primary central nervous system lymphomas (PCNSL), extranodal and nodal lymphomas. PCNSL exhibited diffuse down-regulated profiles, compared to normal peripheral blood lymphocytes. While extranodal and nodal lymphomas also exhibited diffuse down-regulated profiles, some genes displayed up-regulated profiles. Hierarchical clustering analysis separated PCNSL and extranodal lymphomas into distinct groups based on their gene expression profiles, as well as extranodal and nodal, but not PCNSL and nodal. PCNSL exhibited significantly lower expression of BLC/BCA-1 and CCR-3 (Th2 type), and higher expression of IL-8 and MIP-1beta (Th1 type) than extranodal lymphomas. Immunohistochemistry and RT-PCR revealed frequent CCR-3 and BLC/BCA-1 expression in extranodal lymphomas, compared with PCNSL. Our results provide new insights into the pathogenesis of each DLBL. A better understanding of the immune response in each DLBL could help in the design of novel therapeutic strategies based on cytokines/chemokines and their receptors.

Adult↗
PubMed2001

[On the clinical relevance of clozapine-triggered release of cytokines and soluble cytokine-receptors].

Cytokines are pivotal mediators of the interaction between immunocompetent cells. Moreover, they mediate the interaction between the immune system and other physiological systems, including the CNS. It has been shown recently that the antipsychotic drug clozapine stimulates in vivo the release of cytokines and soluble cytokine receptors. This holds true for the tumor necrosis factor(TNF)-system, the interleukin(IL)-2-system, IL-6, and granulocyte colony-stimulating factor (G-CSF). The present paper discusses the clinical relevance of these findings for the pathophysiology of clozapine-induced side-effects. It is very probable that TNF-alpha plays an important role in clozapin-induced fever and in the hematopoetic side effects, including agranulocytosis. Moreover, it is likely that TNF-alpha and other cytokines are involved in metabolic (weight gain, diabetes), cardiac (myocarditis), CNS (sedation) and other rare side effects. The mechanisms underlying clozapine-induced immunomodulation are unknown. Hence, further studies are very important to enhance our understanding of clozapins's side effects and to develop strategies for prevention and treatment.

Antipsychotic Agents↗
PubMed1995

CD34-positive early human thymocytes: T cell receptor and cytokine receptor gene expression.

CD34, a stem cell marker, has been shown to be expressed on human CD3-CD4-CD8- (triple-negative; TN) thymocytes. Phenotypic and functional analyses suggest the following differentiation sequence: CD34+1-3-4-8(-)--> CD34+1+3-4 +/- 8(-)-->CD34-1+3-4+8(+/-)-->CD34-1++3-4+8+. In this report, we examined cytokine receptor gene expression on these subsets by reverse transcription-polymerase chain reaction analysis (RT-PCR). We were able to detect interleukin-7 receptor (IL-7R), c-kit and IL-2R gamma in all CD34+ thymocyte subsets, consistent with previous functional studies. We found IL-1R, granulocyte/macrophage colony-stimulating factor receptor-alpha and IL-4R transcripts in CD3- and CD34+ subsets. Secondly, we investigated T cell receptor (TCR)-delta and -beta gene rearrangement and transcription in CD34+ thymocytes. Our results show that a full-length TCR-delta transcript and the recombination activating genes RAG-1 and RAG-2 mRNA were already expressed in the CD34+1- subset. Mature V beta-containing TCR transcripts were also detected in the CD34+1+ subset, but not in the CD1- fraction. Furthermore, PCR analysis of D-J beta gene rearrangements showed that > or = 70% of CD34+1- cells are in a TCR beta germ-line configuration, although D-J beta recombination had already started in this population.

Antigens, CD34↗
PubMed1995

Regulation of cytokine gene expression: tumor necrosis factor, interleukin-1, and the emerging biology of cytokine receptors.

Cytokines are bioactive molecules which mediate host responses to inflammatory stimuli. For cytokines to exert their effects, a number of molecular processes must occur. Inflammatory cells must sense the presence of a stimulus, often by detection of that stimulus via cell-surface receptors. Information detected at the cell surface must be transduced intracellularly, and the machinery of cytokine messenger RNA and protein synthesis initiated. Once secreted, cytokines must bind specific receptors on target tissues; these receptors in turn transduce signals which alter target cell phenotypes and responses. Each one of these steps is tightly regulated and may serve as a target for therapeutic manipulation. In this article, the regulation of cytokine gene expression is summarized, with particular emphasis on the regulation of tumor necrosis factor alpha and interleukin-1 biosynthesis. Attention is focused on therapeutic agents which alter cytokine production or activity, some of which are currently used in the ICU.

Animals↗
PubMed1999

Neural activities of IL-6-type cytokines often depend on soluble cytokine receptors.

Cytokines of the interleukin-6 (IL-6) family participate in regulatory and inflammatory processes within the nervous system. IL-6, ciliary neurotrophic factor (CNTF) and IL-11 act via specific membrane receptors which, together with their ligands, associate with signal-transducing receptor subunits thereby initiating cytoplasmic signalling. Cells which only express signal-transducing receptor subunits but no ligand binding subunits for IL-6, CNTF and IL-11 are refractory to these cytokines. An unusual feature of the IL-6 cytokine family is that the soluble forms of the ligand binding receptor subunits generated by one cell type in complex with their ligands can directly stimulate the signal-transducing receptor subunits on different cell types which lack ligand binding receptor subunits. This process has been named transsignalling. This article focuses on the importance of transsignalling events in neuronal differentiation and survival responses.

Animals↗
PubMed1993

[Anti-cytokines and anti-cytokine receptors].

Cytokines play a key-role in the immune response. The best known of them is interleukin-2 and its specific receptors. Monoclonal antibodies directed against the interleukin-2 receptor have initially enabled this receptor to be characterized; then they served to confirm the major role played by this cytokine in immune responses, where it proved effective in many animal models such as allograft reaction, delayed hypersensitivity reaction and some experimental auto-immune diseases. These results have been confirmed in man, particularly in kidney transplantation (but also in bone marrow transplantation), and they encourage to develop new bioreagents (chimeral antibodies, "humanized" antibodies, fusion proteins). Some of these reagents are now undergoing evaluation in renal transplantation. The principles of these bioreagents, issued from molecular biology, can be applied to other cytokines involved in the immunopathological mechanisms of certain diseases such as, for example, IL-6 and its role in the development of myeloma. Data from immune intervention directed against other cytokines are, for the moment, preliminary, but many potential targets (IL-1, IL-4, TNF alpha, INF gamma) are emerging.

Animals↗
PubMed2001

EGF receptor crosstalks with cytokine receptors leading to the activation of c-Jun kinase in response to UV irradiation in human keratinocytes.

Ultraviolet (UV) irradiation causes photoageing through induction of matrix-degrading metalloproteinases (MMP), which are upregulated by activator protein-1 (AP-1) (Jun/Fos). The c-Jun kinase activity proves to be critically important in the regulation of AP-1 activity. Our previous studies showed that UV irradiation activates epidermal growth factor receptor (EGFR) and cytokine receptors leading to the activation of c-Jun kinase in cultured human skin keratinocytes in vitro and in human skin in vivo. However, the mechanism of UV-induced cell surface receptor activation and the crosstalk among growth factor receptor and cytokine receptors were not fully investigated. This study showed that UV (30 mJ/cm(2))-induced EGFR tyrosine phosphorylation in a manner similar to EGF (100 ng/ml), or IL-1beta (10 ng/ml) in cultured human keratinocytes. In all cases, EGFR tyrosine phosphorylation was completely inhibited by pretreatment of PD153035 (100 nM, 1 h). Also observed was that UV induced autophosphorylation of interleukin 1 receptor associated kinase (IRAK) in a manner analogous to IL-1beta or EGF. In both UV and EGF cases, the phosphorylation of IRAK was inhibited by pretreatment of PD153035. However, IL-1beta-induced IRAK activation was not affected by PD153035. In vitro kinase assay using GST-c-Jun as a substrate revealed that pretreatment of PD153035 completely inhibited UV- and IL-1-induced c-Jun kinase activity in cultured keratinocytes. Taken together, the above data suggest that EGFR plays dominant role in the crosstalk among growth factor receptor and cytokine receptors leading to the activation of c-Jun kinase upon UV irradiation, and that EGFR could be one of the targets for clinical and cosmetical prevention of UV-induced skin aging.

Adult↗
PubMed1998

Growth-hormone-receptor and cytokine-receptor-family signaling.

Structure of growth-hormone receptor and the class I type of cytokine receptors: common structural features; cytokine-receptor isoforms; oligomerization of receptor components initiates cytokine signalling. Role of the Jak kinases in mediating specific functions of growth-hormone receptor and cytokine receptors. Role of signal transducer and activator of transcription (Stat) proteins in growth hormone and cytokine functions. Other pathways activated by cytokine receptors: the mitogen-activated protein kinase pathway; insulin-receptor substrates 1 and 2 and phosphatidylinositol-3-kinase pathways; the Src pathways and other tyrosine kinase pathways; the phospholipase C/protein kinase C/Ca2+ pathways. Regulation of growth-hormone receptor and cytokine receptor signaling: binding sites, internalization and ubiquitination; phosphatases and Janus kinase/Stat inhibitors. Conclusions and future prospects.

DNA-Binding Proteins↗
PubMed1998

T-lymphocyte functionality assessed by analysis of cytokine receptor expression, intracellular cytokine expression, and femtomolar detection of cytokine secretion by quantitative flow cytometry.

Assessing the functionality of T lymphocytes is important in determining progression rate in human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS), transplant rejection, and autoimmune disease. Activation of T-cells in response to antigen results in expression of cytokines and cytokine receptors, proliferation, and development of effector function. Multiplexed flow cytometric analyses were developed to measure cytokine receptor expression, internal cytokine expression, and cytokine secretion by activated T-cells in vitro. Receptor expression was determined by the binding of phycoerythrin-labeled cytokines. Internal cytokine was determined by intracellular labeling with anti-cytokine antibodies. Cytokine secretion was determined by a flow cytometry-based immunofluorescence assay. The assays could be multiplexed, measuring up to six cytokines simultaneously and measuring cellular receptor expression simultaneously with cytokine secretion. The immunoassays were sensitive in the femtomolar range, allowing determination of normal serum levels of cytokines (<100 fg/ml). Using granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion as a marker for activation, it was determined that at peak secretion (68 h post activation) an average of 1,150 molecules of GM-CSF were produced per cell per hour. Active infection with several viruses reduced the ability of T-cells to be activated. Activated T-cells (1 x 10(6)) normally produced 4-8 pg/ml/h GM-CSF after 20 h of activation, impaired T-function resulted in a decrease to the 0.2-2.0 pg/ml/h range.

Brefeldin A↗
PubMed2004

Regulation of cytokine receptor signaling by nuclear hormone receptors: a new paradigm for receptor interaction.

Cytokine receptors act through a complex signaling network involving Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs) to regulate diverse biological processes controlling growth, development, homeostasis, and immune function. JAK/STAT signaling is terminated by negative regulators including the suppressors of cytokine signaling (SOCSs), protein tyrosine phosphatases, and protein inhibitors of activated STAT. There is a wealth of evidence that nuclear hormone receptors (NHRs) are important regulators of cytokine action. The molecular mechanisms underlying NHR regulation are incompletely understood, but may include control of cytokine production and modulation of the expression and signaling of cytokine receptors. NHRs regulate cytokine receptor signaling by affecting STAT expression and by acting as coregulators of STAT transcriptional action. More recently, NHRs have been shown to exert regulatory effects indirectly through SOCSs, which is a novel mechanism for receptor crosstalk. Better understanding of the regulatory interaction between these two classes of receptors potentially leads to new drug design and/or therapeutic strategies for treatment of cytokine-related diseases.

Gene Expression Regulation↗
PubMed1994

Protein tyrosine phosphorylation in the regulation of hematopoiesis by receptors of the cytokine-receptor superfamily.

Cytokines regulate the growth and differentiation of hematopoietic cells through their interaction with receptors of the cytokine receptor superfamily. This family of receptors has conserved motifs in the extracellular domain but share only limited similarity in the cytoplasmic domains. Although lacking catalytic domains, a variety of studies demonstrate that the cytokine receptors function by coupling ligand binding to induction of tyrosine phosphorylation. Recent studies have shown that the JAK family of kinases associate with cytokine receptors and are activated by ligand binding. Interaction occurs with the membrane proximal region of the cytoplasmic domain, a region that has been found to be essential for mitogenesis. One of the substrates of tyrosine phosphorylation is the receptor and, in the case of the receptor for Epo, the membrane distal region of the cytoplasmic domain is phosphorylated. Once phosphorylated, this site becomes a binding site for the amino-terminal SH2 domain of hematopoietic cell phosphatase (HCP). HCP is an important negative regulator of hematopoietic cell growth and its recruitment to the receptor complex is speculated to be important for this effect. The role of HCP is best indicated by the observation that the murine mutation, motheaten, is due to a mutation that results in the inability to make HCP. Motheaten mice die soon after birth due to the overproliferation of a variety of hematopoietic lineages. Together the results demonstrate an essential role in both protein tyrosine phosphorylation and de-phosphorylation in the growth regulation of hematopoiesis.

Animals↗
PubMed2002

Molecular mechanisms of cytokine receptor activation.

Cytokine receptors are transmembrane proteins that transmit a signal into the cell upon ligand binding. Commonly, these molecules have one hydrophobic segment of about 20-26 amino acids that is believed to span the membrane as a helix and this divides these receptors into extra- and intracellular components. By utilizing two different epitopes, the cytokines bridge two receptor chains, resulting in a close proximity of the intracellular component and thereby initiating the intracellular signalling cascade. The dimerization event is believed to be the mechanism by which the signal is transmitted across a membrane. In the light of new results obtained for the erythropoietin receptor, James A. Wells questioned whether any dimer would be sufficient. This review will expand upon the above question by discussing the more complex signal-transducing receptor subunits of the Interleukin-6 type family of cytokines. Based on the recently solved quaternary structure of the Insulin receptor, possible analogies will be confronted.

Animals↗
PubMed1995

Gene structures of the alpha subunits of human IL-3 and granulocyte-macrophage colony-stimulating factor receptors: comparison with the cytokine receptor superfamily.

Recently, many genes encoding the members of the cytokine receptor superfamily (CRSF), which have common structural features, have been characterized. Analyses on the structures of the genes encoding the alpha subunits of human IL-3 (hIL-3R alpha) and granulocyte-macrophage colony-stimulating factor receptors (hGMR alpha) revealed that they have the structural features common to all members of the CRSF (i.e., conservation of the intron phase pattern as "1-2-1-0-1" rule in the fibronectin type III domains located in extracellular segments of type I cytokine receptor subunits. This finding led us to propose a possible model for gene evolution for the CRSF. We pointed out that the CRSF genes derived from a putative common ancestral gene. In addition to these common features, we found an additional intron that is unique to the IL-3R alpha and the GMR alpha genes. This additional intron suggests that the IL-3R alpha and the GMR alpha genes evolved closely in the evolution process of the CRSF genes. This evidence and results of recent studies on the evolution of mammalian X chromosome make it tempting to speculate that a putative common ancestral gene of the subfamily including IL-3R alpha, GMR alpha, and IL-5R alpha emerged in an autosome at least before the divergence of marsupials and eutherian mammals, early in the 200 million-year history of mammals.

Base Sequence↗
PubMed2002

Cytokine receptor repertoire and cytokine responsiveness of Ho(dull)/Rh(dull) stem cells with differing potentials for G1/S phase progression.

OBJECTIVE: Subsetting of Hoechst 33342 dull (Ho(dull)) hematopoietic stem cells on the basis of rhodamine 123 (Rh) efflux utilizing an improved dual-dye efflux strategy resolves Ho(dull)/Rh(dull) stem cell subsets that differ with regard to their rate of recruitment and progression through the cell cycle upon exposure to cytokines. MATERIALS AND METHODS: Murine bone marrow cells were isolated by negative immunomagnetic selection using lineage-directed antibodies followed by Ho and Rh staining using a dual-dye efflux method. RESULTS: Ho(dull)/Rh(dull) stem cells that efflux Rh more efficiently (R1) exhibit a 4- to 8-hour delay in progression to S phase when stimulated by interleukin-3 (IL-3), IL-6, IL-11, and stem cell factor (SCF) compared to Ho(dull)/Rh(medium) stem cells, which retain low levels of Rh (R2). R1 and R2 cells show a hierarchical entry into S phase upon exposure to any or all of these cytokines. The R1 subset contains proportionately more high proliferative potential colony-forming cells than the R2 subset, but equivalent levels of engraftable stem cells at 3 and 8 weeks after competitive transplantation. Both R1 and R2 cells express c-kit, IL-3R, and IL-11R, whereas IL-6R and c-fms are only expressed by R1 or R2 cells, respectively. Cytokine stimulation of R1 and R2 cells induced cell cycle progression with elevated or induced expression of c-kit, c-fms, IL-2R, and IL-6R. CONCLUSION: These studies indicate that primitive marrow stem cells can be further subsetted by degree of Rh staining to reveal important functional phenotypic differences between cells with different levels of Rh staining.

Animals↗
PubMed1995

SV40-immortalized and primary cultured human retinal pigment epithelial cells share similar patterns of cytokine-receptor expression and cytokine responsiveness.

Retinal pigment epithelial (RPE) cells produce and respond to a variety of cytokines; however, molecular and biochemical studies are restricted by the limited access to large numbers of pure cells and the variability associated with different donor sources. Despite success in establishing primary human RPE (HRPE) cell cultures, the inability to sustain consistent proliferation rates and morphology over several passages remains a concern. This problem was approached by using an immortalized line of simian virus (SV)40 transformed fetal HRPE cells (SVRPE). Cytokine production, receptor expression and responsiveness in the SVRPE cell line was analyzed to determine the usefulness of this model for studying HRPE-cytokine interactions. Using reverse transcriptase polymerase chain reaction (RT-PCR), HRPE and SVRPE cells demonstrated an identical pattern of interleukin-1 receptor (IL-1R), IL-2R (alpha sub-unit), IL-6R, interferon (IFN)-gamma R and tumor necrosis factor-alpha (TNF)R p55 expression. No amplification products for TNFR p75 or granulocyte/macrophage colony stimulating factor (GM-CSF)R were demonstrated in either population. IFN-gamma stimulation induced surface human leukocyte antigen (HLA)-DR in both SVRPE and HRPE, while TNF treatment induced surface expression of intercellular adhesion molecule (ICAM)-1 on SVRPE and upregulated ICAM from basal levels on HRPE. Both cell types showed amplification products for interleukin (IL)-1 beta, IL-6 and transforming growth factor (TGF)-beta 1 using RT-PCR. The bioassays demonstrated that both populations of unstimulated cells constitutively secrete very low levels of TGF-beta and no IL-6.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed2004

Severe cutaneous papillomavirus disease after haemopoietic stem-cell transplantation in patients with severe combined immune deficiency caused by common gammac cytokine receptor subunit or JAK-3 deficiency.

Haemopoietic stem-cell transplantation is a life-saving treatment for severe combined immune deficiency. However, there has been little long-term follow-up of this treatment. There is evidence for the persistance of partial immunodeficiency associated with significant infections, including severe human papillomavirus (HPV) disease. We did a retrospective analysis of severe HPV disease in a group of 41 patients with severe combined immune deficiency from one centre who were alive 10 years or longer after haemopoietic stem-cell transplantation. Nine of the 41 patients had extensive chronic HPV disease limited to the skin, with a median onset at 8 years after transplantation. Four had lesions typical of epidermodysplasia verruciformis, a rare genodermatosis. Transplant characteristics, immune status, and chimerism of these nine patients did not differ significantly from those of the other patients. The nine patients with HPV disease had severe combined immune deficiency associated with either common gammac receptor cytokine subunit or Janus kinase-3 (JAK-3) deficiency. By contrast, patients with other forms of severe combined immune deficiency did not have any signs of HPV disease. That genetic causes are the only predisposing factor to be identified for severe combined immune deficiency, suggests that natural-killer cells or gammac/JAK-3-dependent signalling in keratinocytes could have a role in anti-HPV immunity.

Child↗
PubMed1997

The IFN gamma receptor: a paradigm for cytokine receptor signaling.

During the last several years, the mechanism of IFN gamma-dependent signal transduction has been the focus of intense investigation. This research has recently culminated in the elucidation of a comprehensive molecular understanding of the events that underlie IFN gamma-induced cellular responses. The structure and function of the IFN gamma receptor have been defined. The mechanism of IFN gamma signal transduction has been largely elucidated, and the physiologic relevance of this process validated. Most recently, the molecular events that link receptor ligation to signal transduction have been established. Together these insights have produced a model of IFN gamma signaling that is nearly complete and that serves as a paradigm for signaling by other members of the cytokine receptor superfamily.

Amino Acid Sequence↗