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Paola Romagnani

Publications and source records attributed to Paola Romagnani.

At least 19 recordsLinked to original sources
PubMed2007

PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion.

PF-4/CXCL4 is a member of the CXC chemokine family, which is mainly produced by platelets and known for its pleiotropic biological functions. Recently, the proteic product of a nonallelic variant gene of CXCL4 was isolated from human platelets and named as CXCL4L1. CXCL4L1 shows only 4.3% amino acid divergence in the mature protein, but exhibits a 38% amino acid divergence in the signal peptide region. We hypothesized that this may imply a difference in the cell type in which CXCL4L1 is expressed or a difference in its mode of secretion. In different types of transfected cells, CXCL4 and CXCL4L1 exhibited a distinct subcellular localization and a differential regulation of secretion, CXCL4 being stored in secretory granules and released in response to protein kinase C activation, whereas CXCL4L1 was continuously synthesized and secreted through a constitutive pathway. A protein kinase C-regulated CXCL4 secretion was observed also in lymphocytes, a cell type expressing mainly CXCL4 mRNA, whereas smooth muscle cells, which preferentially expressed CXCL4L1, exhibited a constitutive pathway of secretion. These results demonstrate that CXCL4 and CXCL4L1 exhibit a distinct subcellular localization and are secreted in a differentially regulated manner, suggesting distinct roles in inflammatory or homeostatic processes.

Cells, Cultured↗
PubMed2006

Isolation and characterization of multipotent progenitor cells from the Bowman's capsule of adult human kidneys.

Regenerative medicine represents a critical clinical goal for patients with ESRD, but the identification of renal adult multipotent progenitor cells has remained elusive. It is demonstrated that in human adult kidneys, a subset of parietal epithelial cells (PEC) in the Bowman's capsule exhibit coexpression of the stem cell markers CD24 and CD133 and of the stem cell-specific transcription factors Oct-4 and BmI-1, in the absence of lineage-specific markers. This CD24+CD133+ PEC population, which could be purified from cultured capsulated glomeruli, revealed self-renewal potential and a high cloning efficiency. Under appropriate culture conditions, individual clones of CD24+CD133+ PEC could be induced to generate mature, functional, tubular cells with phenotypic features of proximal and/or distal tubules, osteogenic cells, adipocytes, and cells that exhibited phenotypic and functional features of neuronal cells. The injection of CD24+CD133+ PEC but not of CD24-CD133- renal cells into SCID mice that had acute renal failure resulted in the regeneration of tubular structures of different portions of the nephron. More important, treatment of acute renal failure with CD24+CD133+ PEC significantly ameliorated the morphologic and functional kidney damage. This study demonstrates the existence and provides the characterization of a population of resident multipotent progenitor cells in adult human glomeruli, potentially opening new avenues for the development of regenerative medicine in patients who have renal diseases.

AC133 Antigen↗
PubMed2006

Increase of CXC chemokine CXCL10 and CC chemokine CCL2 serum levels in normal ageing.

No study has evaluated contemporaneously serum CXC and CC chemokines changes in normal ageing. Serum levels of CXCL10 (sCXCL10) (CXC) and CCL2 (sCCL2) (CC) prototype chemokines have been measured in 164 healthy subjects, from 10 to 79 years of age (82 males/82 females). By simple regression analysis, sCXCL10 and sCCL2 were significantly related with increasing age (r=0.32, p<0.001; r=0.31, p<0.0001, respectively), and with each other (r=0.30, p=0.0004). In a multiple linear regression model, only age and sCCL2 were significantly related to sCXCL10 levels (p<0.001); age and sCXCL10 were significantly related to sCCL2 levels (p<0.001). Subjects with high sCXCL10 levels (>150 pg/ml) were not significantly associated with those with high sCCL2 levels (>559 pg/ml). This study, performed in healthy subjects on an age gradient, demonstrates an increase of sCXCL10 and sCCL2 with advancing age; the differential increase of sCXCL10 or sCCL2 may reflect a general shift towards Th1 or Th2 cytokines pattern, respectively.

Adolescent↗
PubMed2006

Increase of interferon-gamma-inducible CXC chemokine CXCL10 serum levels in patients with active Graves' disease, and modulation by methimazole therapy.

BACKGROUND: CXCL10 plays an important role in the initial phases of Graves' disease (GD) and autoimmune thyroiditis (AT); however, until now, CXCL10 serum levels (sCXCL10) in patients with GD have never been evaluated in relation to thyroid function and treatment. OBJECTIVE: To evaluate sCXCL10 in GD. DESIGN: Cross-sectional. PATIENTS: One hundred and three GD, 164 AT, 20 nontoxic multinodular goitre (NTMNG), 16 toxic nodular goitre (TNG) patients and 70 healthy controls (age- and sex-matched). MEASUREMENTS: We measured sCXCL10 in patients and controls, to relate this parameter to the clinical phenotype. RESULTS: Mean sCXCL10 in GD and AT patients were comparable (122+/-81 and 133+/-102 pg/ml) and significantly higher (P<0.01) than in controls or NTMNG patients (73+/- 32 and 76+/- 25 pg/ml, respectively). Hyperthyroid GD had significantly higher sCXCL10 than euthyroid or hypothyroid GD (145+/- 92, 107+/- 56 and 105+/- 46 pg/ml, respectively; P=0.01). GD patients with untreated hyperthyroidism had higher sCXCL10 than hyperthyroid or euthyroid GD patients under methimazole (MMI) treatment (166+/-125, 124+/- 41 and 94+/- 35 pg/ml, respectively; P=0.006). Comparable sCXCL10 levels were observed in newly diagnosed untreated hyperthyroid GD patients with respect to untreated patients with relapse of hyperthyroidism after a previous MMI course (176+/-125, 155+/- 97 pg/ml, respectively). GD had similar sCXCL10 to AT and higher than TNG patients or controls (all age- and sex-matched) (144+/- 81, 149+/- 114, 101+/- 27 and 86+/- 44 pg/ml, respectively; P=0.02). CONCLUSIONS: sCXCL10 is associated with the active phase of GD in both newly diagnosed and relapsing hyperthyroid patients. The reduction in sCXCL10 in treated patients with GD may be related to the immunomodulatory effects of MMI.

Adult↗
PubMed2006

Peripheral blood as a source of stem cells for regenerative medicine.

Converging evidence indicates that peripheral blood (PB) contains stem cells (SCs) with multidifferentiation potential, thus representing a potential source for regenerative medicine in several human disorders, as has also been confirmed by promising results obtained in several preliminary clinical trials. In addition to the classic haematopoietic SCs, PB also harbours endothelial progenitor cells, mesenchymal SCs, tissue-committed SCs and monocyte-like SCs. In spite of a series of different names and/or definitions, a large overlap seems to exist among surface markers, functions and origin of these different SC types. This review analyses the different subsets of SCs described in PB, the different hypotheses suggested to explain their origin, and the possible mechanisms that provide the basis for their biological potential.

Animals↗
PubMed2006

Increased serum CXCL10 in Graves' disease or autoimmune thyroiditis is not associated with hyper- or hypothyroidism per se, but is specifically sustained by the autoimmune, inflammatory process.

OBJECTIVE: Serum CXCL10 (an interferon-gamma-inducible chemokine) levels (sCXCL10) are increased in several autoimmune conditions, including Graves' disease (GD) and autoimmune thyroiditis (AT). Longitudinal assessment of sCXCL10 in autoimmune hypo- or hyperthyroidism has not yet been performed. DESIGN AND METHODS: We longitudinally assayed sCXCL10 in the following groups: thirty-three GD and 11 toxic nodular goiter (TNG) patients when hyperthyroid (Hyper) and when reaching euthyroidism (Eu) with methimazole therapy (MMI) sixty-six AT (33 hypothyroid (Hypo) and 33 Eu) patients, basally and after reaching EU (for Hypo) with levothyroxine (L-T4) therapy twenty-two patients with thyroid cancer (CA) under L-T4-suppressive treatment, of whom 11 were re-evaluated after L-T4 withdrawal for diagnostic WBS, and 11 after recombinant TSH (rhTSH) administration thirty-three healthy controls. RESULTS: At initial evaluation, Hyper GD and AT (Hypo significantly higher than Eu) showed significantly higher mean sCXCL10 than all other groups. MMI treatment led to a significant decrease in sCXCL10 only in GD (not in TNG), while restoration of Eu, in Hypo AT, by L-T4 was not accompanied by significant sCXCL10 change. CA showed sCXCL10 comparable to controls, and both Hypo after L-T4 withdrawal and rhTSH injection had no effect on sCXCL10. CONCLUSIONS: Treatment of Hyper leads to a significant decrease in sCXCL10 only in GD, and this probably depends upon the MMI immunomodulatory effect. L-T4 correction of Hypo is not accompanied by significant modification of sCXCL10 in AT. Increased sCXCL10 is not associated with Hyper or Hypo per se, but is specifically sustained by the autoimmune inflammatory event occurring in both GD and AT.

Adult↗
PubMed2006

Resistin as an intrahepatic cytokine: overexpression during chronic injury and induction of proinflammatory actions in hepatic stellate cells.

Obesity and insulin resistance accelerate the progression of fibrosis during chronic liver disease. Resistin antagonizes insulin action in rodents, but its role in humans is still controversial. The aims of this study were to investigate resistin expression in human liver and to evaluate whether resistin may affect the biology of activated human hepatic stellate cells (HSCs), key modulators of hepatic fibrogenesis. Resistin gene expression was low in normal human liver but was increased in conditions of severe fibrosis. Up-regulation of resistin during chronic liver damage was confirmed by immunohistochemistry. In a group of patients with alcoholic hepatitis, resistin expression correlated with inflammation and fibrosis, suggesting a possible action on HSCs. Exposure of cultured HSCs to recombinant resistin resulted in increased expression of the proinflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, through activation of nuclear factor (NF)-kappaB. Resistin induced a rapid increase in intracellular calcium concentration, mainly through calcium release from intracellular inositol triphosphate-sensitive pools. The intracellular calcium chelator BAPTA-AM blocked resistin-induced NF-kappaB activation and monocyte chemoattractant protein-1 expression. In conclusion, this study shows a role for resistin as an intrahepatic cytokine exerting proinflammatory actions in HSCs, via a Ca2+/NF-kappaB-dependent pathway and suggests involvement of this adipokine in the pathophysiology of liver fibrosis.

Acute Disease↗
PubMed2006

CXCR3 and its binding chemokines in myeloma cells: expression of isoforms and potential relationships with myeloma cell proliferation and survival.

BACKGROUND AND OBJECTIVES: The chemokine receptor CXCR3, involved in chemotaxis, is expressed on normal and malignant B cells and plasma cells. Recent data suggest that CXCR3-binding chemokines may also regulate proliferation and survival in endothelial cells through the interaction with two distinct isoforms of CXCR3 (CXCR3-A and CXCR3-B). DESIGN AND METHODS: We evaluated the potential expression of CXCR3 isoforms in myeloma cells, also investigating whether CXCR3 expression is affected by cell cycle and apoptosis. Furthermore, we assessed the effect of CXCR3 activation on myeloma cell proliferation and survival. RESULTS: We found that CXCR3 is widely expressed on human myeloma cell lines and freshly purified myeloma cells. The presence of both CXCR3 isoforms, CXCR3-A and CXCR3-B, was observed in myeloma cells with different ratios of expression. Interestingly, we found that CXCR3 expression in myeloma cell was cell cycle dependent and that myeloma growth factors inhibited CXCR3 expression in myeloma cells. On the other hand, we found that FAS (CD95)-mediated apoptosis up-regulated CXCR3 expression. A similar behavior was observed for the CXCR3-binding chemokines. Finally we found that the activation of CXCR3 on myeloma cells by CXCL10/IP-10 partially blunted FAS-mediated apoptosis in myeloma cells that express CXCR3-A and that high concentrations of CXCL10/IP-10 inhibit myeloma cell proliferation. INTERPRETATION AND CONCLUSIONS Our data indicate that myeloma cells express the CXCR3 system with patterns correlated to cell cycle and apoptosis and that CXCR3 activation may affect myeloma cell survival and proliferation.

Cell Line, Tumor↗
PubMed2005

Expression of the DNAM-1 ligands, Nectin-2 (CD112) and poliovirus receptor (CD155), on dendritic cells: relevance for natural killer-dendritic cell interaction.

In this study, we demonstrate the involvement of DNAM-1-triggering receptor and its ligands, poliovirus receptor (PVR) and Nectin-2, in natural killer (NK) cell-mediated lysis of dendritic cells (DCs). The surface expression of both ligands was up-regulated in DCs as compared to monocytes. It reached maximal densities after DC maturation induced by different stimuli including lipopolysaccharide (LPS), poly I:C, flagellin, and CD40L. Both immunohistochemical analysis and confocal microscopy revealed expression of DNAM-1 ligands by DCs in lymph nodes in which they were localized in the parafollicular T-cell region and surrounded the high endothelial venules. Remarkably, in cytolytic assays, DNAM-1 cooperated with NKp30 in the NK-mediated killing of both immature and mature DCs and the degree of contribution of DNAM-1 appeared to correlate with the surface densities of its specific ligands PVR and Nectin-2.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2005

Interferon-gamma-inducible alpha-chemokine CXCL10 involvement in Graves' ophthalmopathy: modulation by peroxisome proliferator-activated receptor-gamma agonists.

CONTEXT: CXC alpha-chemokine CXCL10/inducing protein-10 play an important role in the initial phases of autoimmune thyroid disorders. Human thyrocytes in primary culture produce large amounts of CXCL10 when stimulated by interferon-gamma (IFNgamma) and TNFalpha. OBJECTIVE: Serum CXCL10 levels (sCXCL10) were measured in patients with active or inactive Graves' ophthalmopathy (GO). The effects of IFNgamma and TNFalpha stimulation and peroxisome proliferator-activated receptor-gamma (PPARgamma) activation on CXCL10 secretion in primary cultures of thyrocytes, orbital fibroblasts, and preadipocytes were tested. PATIENTS: Sixty consecutive patients with Graves' disease, 60 age- and sex-matched patients with GO, and 60 controls were studied. RESULTS: sCXCL10 was higher (P < 0.0001) in Graves' disease (120 +/- 83 pg/ml; n = 60) and GO (122 +/- 71; n = 60) patients than in age- and sex-matched euthyroid controls (72 +/- 32; n = 60). Among GO patients, sCXCL10 levels were significantly higher in those (n = 14) with active disease (171 +/- 197) than in those with inactive disease (114 +/- 45 pg/ml; P < 0.003). In primary cultures of thyrocytes, retrobulbar fibroblasts and retrobulbar preadipocytes from GO patients, CXCL10 production was absent under basal conditions; dose-dependent secretion of CXCL10 was not induced by TNFalpha alone, whereas stimulation with IFNgamma or TNFalpha plus IFNgamma induced CXCL10 release. Treatment of all cell types with the PPARgamma agonist, rosiglitazone, dose-dependently (0.1-10 microm) suppressed IFNgamma- plus TNFalpha-induced CXCL10 release. CONCLUSIONS: We conclude that in GO, thyrocytes and retrobulbar cell types participate in the self-perpetuation of inflammation by releasing chemokines under the influence of cytokines. PPARgamma activation plays an inhibitory role in this process.

Adult↗
PubMed2005

Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells.

Mesenchymal stem cells (MSCs) inhibit the proliferation of HLA-unrelated T lymphocytes to allogeneic stimulation, but the mechanisms responsible for this activity are not fully understood. We show here that MSCs suppress the proliferation of both CD4+ and CD8+ T lymphocytes, as well as of natural killer (NK) cells, whereas they do not have an effect on the proliferation of B lymphocytes. The antiproliferative effect of MSCs was not associated with any effect on the expression of cell-activation markers, induction of cell apoptosis, or mimicry/enhancement of T regulatory cell activity. The suppressive activity of MSCs was not contact-dependent and required the presence of interferon (IFN)-gamma produced by activated T cells and NK cells. Accordingly, even activated B cells became susceptible to the suppressive activity of MSCs in the presence of exogenously added IFN-gamma. The suppressive effect of IFN-gamma was related to its ability to stimulate the production by MSCs of indoleamine 2,3-dioxygenase activity, which in turn inhibited the proliferation of activated T or NK cells. These findings suggest that the beneficial effect on graft-versus-host disease induced by in vivo coinfusion with the graft of MSCs may be due to the activation of the immunomodulatory properties of MSCs by T cell- derived IFN-gamma.

Apoptosis↗
PubMed2005

CD14+CD34low cells with stem cell phenotypic and functional features are the major source of circulating endothelial progenitors.

Endothelial progenitor cells (EPCs) seem to be a promising tool for cell therapy of acute myocardial infarction, but their nature is still unclear. We show here that EPCs obtainable from peripheral blood (PB) derive from the adhesion-related selection in culture of a subset of CD14+ cells, which, when assessed by the highly-sensitive antibody-conjugated magnetofluorescent liposomes (ACMFL) technique, were found to express CD34. These CD14+CD34low cells represented a variable proportion at individual level of CD14+ cells, ranging from 0.6% to 8.5% of all peripheral-blood leukocytes, and constituted the dominant population among circulating KDR+ cells. By using the ACMFL technique, virtually all CD14+ cells present in the bone marrow were found to be CD14+CD34low double-positive cells. EPCs, as well as purified circulating CD14+CD34low cells, exhibited high expression of embryonic stem cell (SC) markers Nanog and Oct-4, which were downregulated in a STAT3-independent manner when they differentiated into endothelial cells (ECs). Moreover, circulating CD14+CD34low cells, but not CD14+CD34- cells, proliferated in response to SC growth factors, and exhibited clonogenicity and multipotency, as shown by their ability to differentiate not only into ECs, but also into osteoblasts, adipocytes, or neural cells. The results of this study may reconcile apparently contradictory data of the literature, showing the generation of PB-derived EPCs from either CD34+ or CD14+ cells. We suggest that the use of this previously unrecognized population of circulating CD14+CD34low cells, which exhibit both phenotypic and functional features of SCs, may be useful in improving cell-based therapies of vascular and tissue damage.

Antigens, CD↗
PubMed2005

High CXCL10 expression in rejected kidneys and predictive role of pretransplant serum CXCL10 for acute rejection and chronic allograft nephropathy.

BACKGROUND: Several experimental models have shown that CXCL10 is required for initiation and development of graft failure caused by both acute and chronic rejection. METHODS: CXCL10 expression and distribution was investigated in tissue specimens obtained from 22 patients suffering from acute rejection (AR) or chronic allograft nephropathy (CAN) by using in situ hybridization. Furthermore, pretransplantation sera of 316 cadaveric kidney-graft recipients were tested retrospectively for serum CXCL10 levels by a quantitative sandwich immunoassay. RESULTS: Bioptic specimens obtained from patients with CAN were characterized by wide CXCL10 expression not only at level of infiltrating inflammatory cells but also of vascular, tubular, and glomerular structures. In addition, assessment of pretransplant serum CXCL10 levels in 316 graft recipients and stratification of patients in three groups according to serum CXCL10 levels (<100 pg/mL, n=163; 100-150 pg/mL, n=69; >150 pg/mL, n=84) showed highly significant differences in 5-year survival rates for the two extreme groups (95.7% vs. 79.7%, P=0.0002). Accordingly, patients who developed severe, early AR (277.14+/-65.08 p=0.004) and those who developed CAN also showed increased pretransplant serum CXCL10 levels (193.2+/-36.9, P=0.03). Multivariate analysis demonstrated that among the analyzed variables, CXCL10 (relative risk [RR] 2.801) and delayed graft function (RR 3.728) had the highest predictive power of graft loss. CONCLUSIONS: These results suggest that pretransplant serum CXCL10 levels greater than 150 pg/mL confer an increased risk of early, severe, AR and subsequent CAN, finally resulting in renal-allograft failure. This finding might be used for the individualization of immunosuppressive therapies.

Biomarkers↗
PubMed2005

Functional features of human CD25+ regulatory thymocytes.

Two families of Treg cells have been described and named "naturally occurring" and "adaptive" regulatory T cells. The naturally occurring Treg cells arise in the thymus, where they achieve their complete functional maturation, whereas the adaptive Treg cells derive from the thymus too, but achieve their functional maturation in the periphery. This review discusses the phenotype and the functional features of the human naturally occurring CD25+ regulatory thymocytes.

Autoimmune Diseases↗
PubMed2005

Elevated serum interferon-gamma-inducible chemokine-10/CXC chemokine ligand-10 in autoimmune primary adrenal insufficiency and in vitro expression in human adrenal cells primary cultures after stimulation with proinflammatory cytokines.

Chemokines are a large family of cytokines involved in the pathogenesis of inflammatory and autoimmune diseases. Among CXC chemokines, CXC chemokine ligand 10 (CXCL10) has been identified to play an important role in several endocrinological autoimmune diseases, such as Hashimoto's thyroiditis, Graves' disease, and type 1 diabetes mellitus. Although the mechanisms leading to glandular autoimmune process may be at least in part shared by different endocrine organs, the role of CXCL10 in autoimmune adrenal insufficiency is unknown. The aim of this study was to evaluate the role of CXCL10 in Addison's disease (AD). Serum CXCL10 levels were assayed in 64 patients with clinically evident autoimmune AD, 20 patients with autoimmune subclinical AD, nine patients with nonautoimmune AD, and 48 healthy volunteers. Clinically evident and subclinical AD, but not nonautoimmune AD patients, showed a significant increase in serum CXCL10 levels compared with healthy subjects: 119.9 pg/ml (range, 39.8-427.6) and 124.0 pg/ml (range, 37.0-384.7) vs. 75.6 pg/ml (range, 22.4-164.0; P < 0.001 for both groups). Comparable serum CXCL10 levels were found between patients with an isolated form of AD and patients with other autoimmune conditions associated with AD, suggesting a specific influence of the adrenal autoimmune process in determining elevated CXCL10 concentrations in such patients. No relationship was found between serum CXCL10 levels and anti-21-hydroxylase or adrenal cortex autoantibody titers or between CXCL10 levels and duration of disease. The role of CXCL10 in the adrenal gland was also evaluated in vitro in human zona fasciculata cells (hZFC). CXCL10, although not basally detected in cultured hZFC, was strongly induced by interferon-gamma and synergistically increased by TNF-alpha addition. Hydrocortisone or ACTH alone had no effect on CXCL10 secretion in hZFC, but they both significantly inhibited cytokine-induced CXCL10 secretion. Taken together, these data suggest a potential role of hZFC, through the production of CXCL10, in regulating the recruitment of specific subsets of activated lymphocytes in autoimmune AD.

Addison Disease↗
PubMed2005

Thymic regulatory T cells.

Several types of T regulatory (Treg) cells have been described in both mice and humans, including natural or professional (CD4+CD25+ T cells) and adaptive (Th3 and Tr1 cells) Treg cells. The former develops in the thymus and results in an endogeneous long-lived population of self-antigen-specific T cells in the periphery poised to prevent potentially autoimmune reactions. The second subset develops as a consequence of activation of mature T cells under particular conditions of sub-optimal antigen exposure and/or costimulation. Natural Treg cells are positively selected in the cortex through their TCR interactions with self-peptides presented by thymic stromal cells. It is likely that this high-affinity recognition results in signals rendering them anergic and able to produce anti-apoptoptic molecules which protect them from negative selection. Recently, small subsets of CD4+CD25+ and of CD8+CD25+ cells sharing similar characteristics have been detected in human fetal and post-natal thymuses. Both CD4+CD25+ and CD8+CD25+ human thymocytes express Foxp3 and GITR mRNA, as well as surface CCR8 and TNFR2 and cytoplasmic CTLA-4 proteins, which are common features of mature Treg cells. Following activation they do not proliferate or produce cytokines, but express surface CTLA-4 and TGF-beta1. They suppress the proliferation of autologous CD4+CD25- thymocytes to allogeneic stimulation by a contact-dependent mechanism related to the combined action of surface CTLA-4 and TGF-beta leading to the inhibition of the IL-2R alpha chain on target T cells. Lastly, both CD4+CD25+ and CD8+CD25+ Treg thymocytes exert strong suppressive activity on Th1, but much lower on Th2 cells, since these latter may escape from suppression via their ability to respond to growth factors other than IL-2. Treg cells that develop in, and emerge from, the thymus are certainly responsible for the maintenance of self-tolerance and prevention of autoimmune disorders. The result that Th1 cells are highly susceptible to the suppressive activity of Treg thymocytes is consistent with the important role of these cells in protecting against the Th1-mediated immune response to autoantigens.

Animals↗
PubMed2005

CXCR3-mediated opposite effects of CXCL10 and CXCL4 on TH1 or TH2 cytokine production.

BACKGROUND: Two variants of the CXCR3 receptor exist, one (CXCR3-A) reactive with CXCL9, CXCL10, and CXCL11 and the other (CXCR3-B) also reactive with CXCL4. Both variants are contemporarily expressed by human T cells. OBJECTIVE: We sought to investigate the in vitro effects of CXCL10 and CXCL4 on the production of TH1 or TH2 cytokines. METHODS: The cytokine profile of antigen-specific human CD4+ T-cell lines obtained in the absence or presence of CXCL10 or CXCL4 was evaluated by means of quantitative RT-PCR, flow cytometry, and ELISA. RESULTS: CXCL10 upregulated IFN-gamma and downregulated IL-4, IL-5, and IL-13 production, whereas CXCL4 downregulated IFN-gamma and upregulated TH2 cytokines. Similar effects were also observed on polyclonally activated pure naive CD4+ T cells. The opposite effects of CXCL10 and CXCL4 on TH1 and TH2 cytokine production were inhibited by an anti-CXCR3 antibody able to neutralize both CXCR3-A and CXCR3-B and were apparently related to the activation of distinct signal transduction pathways. Moreover, CXCL10 upregulated mRNA levels of T-box expressed in T cells and downregulated GATA-3 expression, whereas CXCL4 downregulated T-box expressed in T cells and upregulated GATA-3. Finally, CXCL4, but not CXCL10, induced direct activation of IL-5 and IL-13 promoters. CONCLUSION: CXCL10 and CXCL4 exert opposite effects on the production of human TH1 and TH2 cytokines, likely through their respective interaction with CXCR3-A or CXCR3-B and the consequent activation of different signal transduction pathways. This might represent an internal regulatory pathway of TH cell responses and might contribute to the modulation of chronic inflammatory reactions, including allergy.

CD4-Positive T-Lymphocytes↗