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At least 109 records · Page 6Linked to original sources
PubMed2006

Inositol 1,4,5-trisphosphate IP(3) receptors and their role in neuronal cell function.

Inositol 1,4,5-trisphosphate (IP(3)) receptor is a Ca(2+) release channel localized on the endoplasmic reticulum (ER) and plays an important role in neuronal function. IP(3) receptor was discovered as a developmentally regulated protein missing in the cerebellar mutant mice. Recent studies indicate that IP(3)Rs are involved in early development and neuronal plasticity. IP(3) works to release IRBIT from the IP(3) binding core in addition to release Ca(2+). IRBIT binds to and activates Na, Bicarbonate cotransporter. Electron microscopic study show the IP(3) receptor has allosteric property to change its form from square to windmill in the presence of Ca(2+). IP(3)R associates with ERp44, a redox sensor, Homer, other proteins and is transported as vesicular ER on microtubules. All these data suggests IP(3) receptor/CA(2+) channel works as a signaling center inside cells.

Animals↗
PubMed2005

Identification and characterization of novel IGFBP5 interacting protein: evidence IGFBP5-IP is a potential regulator of osteoblast cell proliferation.

Insulin-like growth factor binding protein-5 (IGFBP5) is a multifunctional protein, which acts not only as a traditional binding protein, but also functions as a growth factor independent of IGFs to stimulate bone formation. It has been predicted that the intrinsic growth factor action of IGFBP5 involves binding of IGFBP5 to a putative receptor to induce downstream signaling pathways and/or nuclear translocation of IGFBP5 to influence transcription of genes involved in osteoblast cell proliferation/differentiation. Our study indentified proteins that bound to IGFBP5 using IGFBP5 as bait in a yeast two-hybrid screen of the U2 human osteosarcoma cell cDNA library. One of the clones that interacted strongly with the bait under high-stringency conditions corresponded to a novel IGFBP5 interacting protein (IGFBP5-IP) encoded by a gene that resides in mouse chromosome 10. The interaction between IGFBP5-IP and IGFBP5 is confirmed by in vitro coimmunoprecipitation studies that used pFlag and IGFBP5 polyclonal antibody, and cell lysates overexpressing both IGFBP5-IP and IGFBP5. Northern blot and RT-PCR analysis showed that the IGFBP-IP is expressed in both untransformed normal human osteoblasts and in osteosarcoma cell lines, which are known to produce IGFBP5. To determine the roles of IGFBP5-IP, we evaluated the effect of blocking the expression of IGFBP5-IP on osteoblast proliferation. We found that using a IGFBP5-IP-specific small interfering-hairpin plasmid resulted in a decrease in both basal and IGFBP5-induced osteoblast cell proliferation. On the basis of these findings, we predict that IGFBP5-IP may act as intracellular mediator of growth promoting actions of IGFBP5 and perhaps other osteoregulatory agents in bone cells.

Amino Acid Sequence↗
PubMed2001

Functional overlap of IP(3)- and cADP-ribose-sensitive calcium stores in guinea pig myenteric neurons.

In myenteric neurons two different receptor subtypes govern the intracellular Ca(2+) stores: the inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R) and the ryanodine receptor (RyR). Their degree of functional overlap was determined by examining Ca(2+) release in these cells through both superfusion techniques and intracellular microinjection. Microinjection of IP(3) (50 microM) and cADP-ribose (cADPr, 50 microM), specific ligands for the IP(3)R and RyR, respectively, demonstrated mobilization of intracellular Ca(2+) stores. Perfusion with cinnarizine (50 microM) or dantrolene (10 microM), antagonists of the IP(3)R and RyR, respectively, eliminated the Ca(2+) response to microinjected IP(3) and cADPr. Superfusion of the neurons with 100 microM ATP, an IP(3)-mediated Ca(2+)-mobilizing agonist, caused intracellular Ca(2+) increments, which were antagonized by cinnarizine, and the RyR antagonists dantrolene, procaine (5 mM), and ryanodine (1 microM). Caffeine (10 mM) was applied repetitively in Ca(2+)-free conditions to deplete RyR-sensitive stores; subsequent perfusion with ATP demonstrated a Ca(2+) response. Conversely, caffeine caused a Ca(2+) response after repetitive ATP exposures. The internal Ca(2+) stores of myenteric neurons are governed by two receptor subtypes, IP(3)R and RyR, which share partial functional overlap.

Adenosine Diphosphate Ribose↗
PubMed2003

Increased IP-10 and MIG expression after intra-amniotic endotoxin in preterm lamb lung.

Subtraction hybridization was performed to explore changes in gene expression in the fetal lung after 20 mg of intra-amniotic (IA) endotoxin. Interferon-gamma-inducible 10-kd protein (IP-10) and monokine induced by interferon-gamma (MIG) constituted 20% of 102 endotoxin-induced clones identified in the preterm lamb lung. IP-10 (CXCL10) and MIG (CXCL9) are T-cell chemoattractants that have angiostatic properties. Both IP-10 and MIG mRNA were induced 30- to 40-fold in the fetal lung at 1 to 2 days after IA endotoxin. Intense IP-10 mRNA expression was detected by in situ hybridization in the bronchiolar and peribronchiolar areas and the vascular endothelium after IA endotoxin at all time points tested. MIG mRNA expression was detected initially focally in infiltrating neutrophils (15 hours after IA endotoxin) and later in the bronchiolar and peribronchiolar areas and vascular endothelium (1 day after IA endotoxin). In contrast to endotoxin, IA tumor necrosis factor-alpha or interleukin-1 alpha did not induce IP-10 or MIG mRNA in the lung. IA endotoxin also caused a modest induction of IP-10 and MIG mRNA in the jejunum, liver, and spleen. The IP-10 and MIG receptor CXCR3 was detected in the bronchiolar epithelium of preterm lambs by immunostaining. IP-10 and MIG are potent angiostatic chemokines that may contribute to lung injury and altered pulmonary vascular development in the preterm exposed to chorioamnionitis.

Amnion↗
PubMed2001

Thyrocytes from autoimmune thyroid disorders produce the chemokines IP-10 and Mig and attract CXCR3+ lymphocytes.

To better understand the selective migration of lymphocytes in autoimmune thyroid disorders (AITDs), we analyzed thyroid samples and demonstrated an enhanced expression of the chemokines interferon (IFN)-inducible protein (Ip)-10 and regulated on activation normal T lymphocyte expressed and secreted (RANTES) in thyroids from AITD patients. Ip-10 and monokine induced by IFN-gamma (Mig) were expressed in vivo in thyroid follicular cells (TFCs) from AITD thyroids. Interestingly, Ip-10 mRNA, although not basally detected in cultured TFCs, was strongly induced by IFN-gamma and synergistically increased by TNF-alpha addition. Furthermore, high levels of Ip-10 protein were detected in the supernatants of IFN-gamma-stimulated TFCs. Likewise, Mig protein was strongly induced in TFCs by the same stimuli as Ip-10. Unlike Ip-10 and Mig, the expression of RANTES was induced mainly by TNF-alpha. In addition, intrathyroidal lymphocytes from AITD patients showed higher expression of CXCR3, CCR2, and CCR5 chemokine receptors than autologous peripheral blood lymphocytes. T lymphoblasts expressing CXCR3 showed an increased migration to supernatants from stimulated TFCs, which was abolished by specific antibodies to the chemokines Ip-10 and Mig, as well as to their receptor CXCR3. Taken together, these data suggest a potential role of TFCs, through the production of the chemokines Ip-10, Mig and RANTES, in regulating the recruitment of specific subsets of activated lymphocytes in AITDs.

Cell Movement↗
PubMed2002

IP-10 and Mig production by glomerular cells in human proliferative glomerulonephritis and regulation by nitric oxide.

High levels of expression of mRNA and protein for the chemokines interferon-gamma (IFN-gamma)-inducible protein of 10 kD (IP-10) (CXCL10) and the monokine induced by IFN-gamma (Mig) (CXCL9) were observed, by using in situ hybridization and immunohistochemical analyses, in kidney biopsy specimens from patients with glomerulonephritis (GN), particularly those with membranoproliferative or crescentic GN, but not in normal kidneys. Double-immunostaining or combined in situ hybridization and immunohistochemical analyses for IP-10, Mig, and proliferating cell nuclear antigen (PCNA) or alpha-smooth muscle actin (alpha-SMA) revealed that IP-10 and Mig production by resident glomerular cells was a selective property of glomeruli in which mesangial cells demonstrated active proliferation. IP-10 and Mig mRNA and protein were also expressed by primary cultures of human mesangial cells and human visceral epithelial cells after stimulation with IFN- gamma or with IFN-gamma plus tumor necrosis factor-alpha (TNF-alpha) (which produced greater stimulation). The induction of IP-10 and Mig mRNA and protein expression by IFN-gamma plus TNF-alpha was strongly inhibited by nitric oxide (NO) donors, such as sodium nitroprusside or S-nitroso-N-acetylpenicillamine, but not by cGMP analogues. Electrophoretic mobility shift assays demonstrated that NO donors repressed IP-10 gene transcription induced by IFN-gamma plus TNF-alpha through the inhibition of NF-kappaB activation. These data demonstrate that resident glomerular cells in kidneys of patients with proliferative GN produce large amounts of IP-10 and Mig, which may play important pathogenic roles in this disease. These data also indicate that the production of IP-10 and Mig by human mesangial cells can be downregulated by NO donors through cGMP-independent inhibition of NF-kappaB activation.

Cells, Cultured↗
PubMed2004

[Reusable imaging plate (IP) for swift and automatic measurement of X-ray CT dose profiles].

PURPOSE: In multi-slice CT, over beaming by penumbra effect has been reported, and measurements of X-ray CT beam profiles are very important for accurate performance assessment. This study was conducted in order to facilitate and economize on the measurement of CT dose profiles. METHODS: The imaging plate (IP: HR-V type, Fuji) was placed in its case, X-rayed, and then read with a digital IP reader, which then erased the data in preparation for reuse. The values were then compared with the values obtained with the standard one-use imaging film. The CT scanner used was a Toshiba Aquilion Multi (4 rows). RESULTS: The shape of the beam profile obtained using the IP method was for all practical purposes identical to that obtained using the film method. The FWHM values for 2.0, 4.0, 8.0, 12.0, 16.0, 20.0 and 32-mm beam were 4.88, 6.61, 10.2, 14.9, 18.2, 22.4 and 35.0 mm for the IP method and 4.81, 6.66, 10.2, 14.7, 18.1, 22.3 and 34.8 mm for the film method. In addition, in the IP method, the results obtained for the shape of the beam profile and the FWHM were found to be extremely similar irrespective of the X-ray tube used or individual differences between IPs. CONCLUSION: We have developed a new X-ray CT beam profile measurement system using an IP. This IP method permits data processing to be performed entirely in the digital domain, allowing high-precision measurements to be obtained with ease.

Equipment Reuse↗
PubMed1999

The T cell-specific CXC chemokines IP-10, Mig, and I-TAC are expressed by activated human bronchial epithelial cells.

Recruitment of activated T cells to mucosal surfaces, such as the airway epithelium, is important in host defense and for the development of inflammatory diseases at these sites. We therefore asked whether the CXC chemokines IFN-induced protein of 10 kDa (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T-cell alpha-chemoattractant (I-TAC), which specifically chemoattract activated T cells by signaling through the chemokine receptor CXCR3, were inducible in respiratory epithelial cells. The effects of proinflammatory cytokines, including IFN-gamma (Th1-type cytokine), Th2-type cytokines (IL-4, IL-10, and IL-13), and dexamethasone were studied in normal human bronchial epithelial cells (NHBEC) and in two human respiratory epithelial cell lines, A549 and BEAS-2B. We found that IFN-gamma, but not TNF-alpha or IL-1 beta, strongly induced IP-10, Mig, and I-TAC mRNA accumulation mainly in NHBEC and that TNF-alpha and IL-1 beta synergized with IFN-gamma induction in all three cell types. High levels of IP-10 protein (> 800 ng/ml) were detected in supernatants of IFN-gamma/TNF-alpha-stimulated NHBEC. Neither dexamethasone nor Th2 cytokines modulated IP-10, Mig, or I-TAC expression. Since IFN-gamma is up-regulated in tuberculosis (TB), using in situ hybridization we studied the expression of IP-10 in the airways of TB patients and found that IP-10 mRNA was expressed in the bronchial epithelium. In addition, IP-10-positive cells obtained by bronchoalveolar lavage were significantly increased in TB patients compared with normal controls. These results show that activated bronchial epithelium is an important source of IP-10, Mig, and I-TAC, which may, in pulmonary diseases such as TB (in which IFN-gamma is highly expressed) play an important role in the recruitment of activated T cells.

Bronchi↗
PubMedDate not supplied

Expression of the chemokines IP-10 and Mig in IL-10 transduced tumors.

Several laboratories have reported marked tumor inhibition when the cytokine interleukin-10 (IL-10) is overexpressed as a transgene in a variety of tumor cells. To identify critical effector molecules, we compared the expression of the chemokine crg-2, the murine homolog of human inducible protein 10 (human IP-10) in murine mammary tumors derived from the transplantation of six IL-10 expressing clones of tumor cell line 66.1, parental 66.1, or 66-neo-cells. We observed increased levels of IP-10 mRNA in all IL-10-expressing tumors examined in comparison to 66-neo. IP-10 mRNA was not detected in parental 66.1 tumors. The closely related chemokine Mig (monokine induced by interferon-gamma [IFN-gamma]) was also induced in all IL-10-expressing tumors. Studies of cultured tumor cells in vitro show that mammary epithelial tumor cells, in the absence of host elements, can express IP-10 and Mig in response to induction with either lipopolysaccharide (LPS) or IFN-gamma alone. The combination of LPS plus IFN-gamma resulted in even greater induction of IP-10 RNA. The kinetics of induction differ somewhat for the two chemokines, with IP-10 showing slower induction and less rapid decline. Because both Mig and IP-10 are chemotactic for tumor-infiltrating lymphocytes, we examined the presence of CD4+ and CD8+ lymphocytes in these tumors. Consistent with the upregulation of Mig and IP-10, we saw significantly increased numbers of CD8+ cells and a lesser increase in CD4+ cells in tumors with elevated levels of both chemokines.

Animals↗
PubMed2001

Expression of the Chemokines IP-10 and Mig in IL-10 Transduced Tumors.

SUMMARY: Several laboratories have reported marked tumor inhibition when the cytokine interleukin-10 (IL-10) is overexpressed as a transgene in a variety of tumor cells. To identify critical effector molecules, we compared the expression of the chemokine crg-2, the murine homolog of human inducible protein 10 (human IP-10) in murine mammary tumors derived from the transplantation of six IL-10 expressing clones of tumor cell line 66.1, parental 66.1, or 66-neo-cells. We observed increased levels of IP-10 mRNA in all IL-10-expressing tumors examined in comparison to 66-neo. IP-10 mRNA was not detected in parental 66.1 tumors. The closely related chemokine Mig (monokine induced by interferon-gamma [IFN-gamma]) was also induced in all IL-10-expressing tumors. Studies of cultured tumor cells in vitro show that mammary epithelial tumor cells, in the absence of host elements, can express IP-10 and Mig in response to induction with either lipopolysaccharide (LPS) or IFN-gamma alone. The combination of LPS plus IFN-gamma resulted in even greater induction of IP-10 RNA. The kinetics of induction differ somewhat for the two chemokines, with IP-10 showing slower induction and less rapid decline. Because both Mig and IP-10 are chemotactic for tumor-infiltrating lymphocytes, we examined the presence of CD4+ and CD8+ lymphocytes in these tumors. Consistent with the upregulation of Mig and IP-10, we saw significantly increased numbers of CD8+ cells and a lesser increase in CD4+ cells in tumors with elevated levels of both chemokines.

Journal Article↗
PubMed1994

Cloning and expression of a cDNA for the human prostanoid IP receptor.

A cDNA clone coding for a functional human prostanoid IP receptor has been isolated from a lung cDNA library. The human IP receptor consists of 386 amino acid residues with a predicted molecular mass of 40,961, and has the seven putative transmembrane domains characteristic of G-protein-coupled receptors. Challenge of Xenopus oocytes co-expressing the IP receptor and the cystic fibrosis transmembrane conductance regulator (cAMP-activated Cl- channel) with the stable prostacyclin analog iloprost resulted in specific inward Cl- currents, demonstrating that the cDNA encoded a functional IP prostanoid receptor coupled to elevation in cAMP. Radioreceptor binding studies using membranes prepared from mammalian COS cells transfected with the IP receptor cDNA showed that the rank order of potency for prostaglandins and prostaglandin analogs in competition for [3H]iloprost specific binding sites was as predicted for the IP receptor, with iloprost >> carbacyclin >> prostaglandin (PG) E2 > PGF 2 alpha = PGD2 = U46619. Northern blot analysis showed that IP mRNA was most abundantly expressed in kidney, with lesser amounts detected in lung and liver. In summary, we have cloned and expressed a cDNA for the human prostanoid IP receptor that is functionally coupled to a signaling pathway involving stimulation of intracellular cAMP production.

Amino Acid Sequence↗
PubMedDate not supplied

Delayed wound healing and disorganized neovascularization in transgenic mice expressing the IP-10 chemokine.

IP-10 is a member of the alpha or cysteine-X amino acid-cysteine (CXC) chemokine family of chemotactic cytokines. High levels of IP-10 expression have been detected in a number of chronic human inflammatory conditions, including psoriasis, a common inflammatory disease of the skin. IP-10 has been shown to chemoattract activated T cells, inhibit the proliferation of endothelial cells, and inhibit the growth of tumors in vivo. To determine the capacity of IP-10 to modulate the inflammatory response in vivo, we have created transgenic mice that constitutively express IP-10 from keratinocytes. These mice developed normally and, in general, did not spontaneously recruit leukocytes into the skin or other organs that expressed the transgene. In addition, the transgenic mice had a normal cutaneous contact hypersensitivity cellular immune response. However, IP-10 transgenic mice had an abnormal wound healing response characterized by a more intense inflammatory phase and a prolonged and disorganized granulation phase with impaired blood vessel formation. These results have demonstrated that IP-10 can inhibit the neovascularization associated with a physiological response in vivo and have revealed a novel biologic activity of IP-10 as an inhibitor of wound healing.

Animals↗
PubMed1998

Involvement of the IP-10 chemokine in sarcoid granulomatous reactions.

The accumulation of T cells and monocytes at sites of ongoing inflammation represents the earliest step in the series of events that lead to granuloma formation in sarcoidosis. In this study, we evaluated the pulmonary production of IFN-inducible protein 10 (IP-10), a CXC chemokine that stimulates the directional migration of activated T cells. Striking levels of IP-10 were demonstrated in the bronchoalveolar lavage (BAL) fluid of 24 patients with pulmonary sarcoidosis and lymphocytic alveolitis, as compared with patients with inactive disease or control subjects. A positive correlation was demonstrated between IP-10 levels and the number of sarcoid CD45R0+/CD4+ cells in the BAL. Immunochemistry, performed with an anti-human IP-10 polyclonal Ab in lymph nodes displaying prominent sarcoid granulomas, showed that cells bearing IP-10 were mainly epithelioid cells and CD68+ macrophages located inside granulomatous areas. Macrophages recovered from the BAL of sarcoid patients stained positive for IP-10 protein. Furthermore, alveolar macrophages isolated from sarcoid patients with T cell alveolitis and cultured for 24 h in presence of IFN-gamma secreted definite levels of IP-10 capable of inducing T cell chemiotaxis. Interestingly, alveolar lymphocytes recovered from patients with active sarcoidosis were CD4+ T cells expressing Th1 cytokines (IL-2 and IFN-gamma) and high levels of CXCR3. Taken together, these data suggest the potential role of IP-10 in regulating the migration and activation of T cells toward sites of sarcoid inflammatory process and the consequent granuloma formation.

Adult↗
PubMed1998

Interleukin-10 suppresses IP-10 gene transcription by inhibiting the production of class I interferon.

Interleukin-10 (IL-10) selectively inhibited lipopolysaccharide (LPS)-induced chemoattractant cytokine gene expression: levels of IP-10 mRNA were markedly suppressed in IL-10-treated mouse peritoneal macrophages, whereas the expression of the RANTES mRNA was only modestly reduced. IL-10 inhibited IP-10 mRNA accumulation by reducing IP-10 gene transcription as demonstrated by nuclear run-on analysis. Interestingly, the ability of IL-10 to inhibit expression of IP-10 was dependent on the inducing stimulus; IL-10 did not suppress interferon gamma (IFNgamma)- or IFNbeta-stimulated IP-10 transcription or mRNA accumulation. These results suggested that IL-10 might act indirectly to suppress IP-10 expression by inhibiting LPS-induced class I IFN production. This hypothesis was supported by the following observations. First, LPS-induced IP-10 mRNA expression was blocked in cells cotreated with cycloheximide. Second, IL-10 inhibited the production of IFN/beta-mediated antiviral activity. Finally, the IL-10-mediated suppression of LPS-stimulated IP-10 production could be rescued by cotreatment with IFNbeta.

Animals↗
PubMed1999

Differential expression and regulation of chemokines JE, KC, and IP-10 gene in primary cultured murine hepatocytes.

Chemokines are a superfamily of structurally related chemoattractant cytokines. JE (monocyte chemoattractant protein-1) and IP-10 (interferon-inducible protein-10) have been detected in the diseased liver. However the in vitro expression is unclear. In this report, we revealed that JE, KC (melanoma growth-stimulating activity gene), and IP-10 mRNAs are not expressed in the normal liver but spontaneously and time-dependently expressed in the primary hepatocytes. The serum-independent gene expression of both JE and KC lasted over 72 h, but that of IP-10 became undetectable 24 h after isolation with collagenase perfusion method. The induction of the genes' expression was not due to LPS contamination but nevertheless was associated with isolation procedure. Actinomycin D blocked their expression. The increase of their transcripts resulted from greater increase in gene transcription and lower mRNA stability. Consistent with c-jun, their mRNA expressions were simultaneously superinduced by cycloheximide (1 microg/ml), suggesting that de novo protein synthesis is involved their transcriptions. Inhibition by pyrrolidine dithiocarbamate (PDTC), a NF-kappaB/c-rel inhibitor, and EMSA imply that NF-kappaB/c-rel is important in their expressions. Of particular interest is that dexamethasone upregulated the spontaneous expression of KC, but suppressed that of JE and IP-10. LPS upregulated the mRNA levels of JE and KC but did not affect that of IP-10. IFN-gamma induced the expression of IP-10; however unlike in macrophages, it did not selectively inhibit that of JE and KC. Our data demonstrated the existence and differential gene expression of JE, KC, and IP-10 in primary cultured hepatocytes, and these are considered to be a reflex of the alteration of hepatocyte cellular physiology during and after isolation.

Animals↗
PubMed2005

The Epstein-Barr virus oncoprotein latent membrane protein 1 induces expression of the chemokine IP-10: importance of mRNA half-life regulation.

The latent membrane protein 1 (LMP1) of Epstein-Barr Virus (EBV) is the main inducer of immuno-modulatory molecules affecting growth and survival of EBV-infected cells. However, the network of signalling pathways involved remains to be elucidated. Here we show that LMP1 may regulate cellular genes like IFN-gamma-inducible protein-10 kDa (IP-10) not only through transcriptional but also post-transcriptional mechanisms. LMP1-mediated IP-10 expression is independent from IFN-gamma, TNF-alpha or IL-18. Transcriptional activation of IP-10 by LMP1 or CD40 stimulation depends on an NF-kappaB motif within the proximal 435 bp fragment. Carboxy-terminal activating regions 1 or 2 of LMP1 are sufficient to direct IP-10 promoter activation. IP-10 induction is inhibited by blockade of p38/SAPK2 with SB 202190, which results in decreased IP-10 mRNA half-life without affecting IP-10 promoter activity. Thus, LMP1-mediated p38/SAPK2 activation regulates transcript stability. This new mechanism of gene regulation demonstrates the potential of the oncoprotein LMP1 to orchestrate a network of signalling pathways at different regulatory levels including mRNA stability.

Amino Acid Motifs↗
PubMed2003

Expression of the chemokine IP-10 correlates with the accumulation of hepatic IFN-gamma and IL-18 mRNA in chronic hepatitis C but not in hepatitis B.

The pathogenesis of hepatitis C virus-induced chronic liver disease is still poorly understood. Previous studies revealed enhanced hepatic expression of the Th1 prototype cytokine IFN-gamma in individuals with chronic hepatitis C. In accordance with several animal models of experimentally induced hepatitis, a Th1 lymphocyte driven inflammatory process, which involves newly infiltrated as well as resident monocytes/macrophages, has been proposed. An involvement of the interferon-gamma-inducible chemokine IP-10, which is chemoattractive for stimulated Th1 cells and monocytes, is also suggested. Using an HBV transgenic mouse model, a reduction of hepatic infiltration and liver disease was achieved recently by administration of antibodies directed against the interferon-gamma-inducible chemokine Mig and against IP-10. In the present study, expression of IP-10 was investigated both in serum and in the liver of patients with chronic hepatitis C and hepatitis B. Patients with liver diseases of non-viral etiologies served as controls. IP-10 expression was highest in hepatitis C. In chronic hepatitis C, but not in chronic hepatitis B nor in liver disorders unrelated to viral infections, IP-10 expression was strongly correlated with the amount of transcripts for IFN-gamma and to the amount of transcripts for the constitutively expressed macrophage derived cytokine IL-18. Hepatic inflammatory activity, however, was found to be associated more closely with IFN-gamma than with IP-10 or IL-18 mRNA expression. The data support the hypothesis that IP-10 is responsible for the recruitment of Th cells and monocytes in chronic hepatitis C, and suggest that its role in chronic hepatitis B is less determining. Moreover, they deliver additional support for the view that IFN-gamma still has to be considered as a mediator that determines the outcome of inflammation, e.g., via its ability to activate IL-18 expressing cells and to initiate a delayed type hypersensitivity reaction.

Adolescent↗
PubMed2002

Expression of CXC chemokine IP-10 in testicular germ cell tumours.

Tumour-infiltrating T lymphocytes (TILs) possess discrepant properties ranging from anti- to protumour activities. Understanding precisely which mechanisms navigating T lymphocytes into the tumour site will help to further the anti-tumour or to disrupt the pro-tumour activities of TILs. The present study asked what enables TILs to migrate into testicular germ cell tumours (TGCTs). TILs were characterized and the expression of a large panel of T-lymphocyte-attracting chemokines was investigated in 21 TGCT cases. Flow cytometry revealed that approximately 80% of TGCT-infiltrating T lymphocytes express CXCR3, a receptor for the chemokine interferon-inducible protein-10 (IP-10). RT-PCR and immunohistochemistry indicated that IP-10 was the only chemokine investigated which was constantly expressed in TGCT. As IP-10 was found to be expressed by endothelial cells of TGCT-associated blood vessels, the question arose whether the IP-10-regulating cytokine interferon-gamma (IFNgamma) is produced by tumour cells and if so, whether tumour-derived IFNgamma can induce IP-10 in endothelial cells. Applying in situ hybridization, IFNgamma transcripts were found in neoplastic germ cells. Analyses of two TGCT cell lines indicated that the tumour cells not only express IFNgamma mRNA, but also produce and secrete IFNgamma protein; tumour-derived IFNgamma provokes IP-10 expression and secretion by endothelial cells in vitro, as assessed by PCR and ELISA. Together, the data suggest that neoplastic germ cells secret IFNgamma and thereby stimulate tumour-associated endothelial cells to express IP-10, which contributes to the recruitment of CXCR3+ T lymphocytes to the site of TGCTs.

Adult↗