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J Favero

Publications and source records attributed to J Favero.

At least 19 recordsLinked to original sources
PubMed2000

Tumor necrosis factor-alpha production is differently regulated in gamma delta and alpha beta human T lymphocytes.

Tumor necrosis factor-alpha (TNF-alpha) plays a crucial role in the early defense against pathogens. This cytokine is produced by several cell types including T lymphocytes expressing the alphabeta as well as the gammadelta T cell receptor (TcR). In human, the circulating gammadelta T cells, which mostly express Vgamma9Vdelta2 TcR, have been strongly suggested to play an important protective role against infectious agents. These activated cells early produce high amounts of TNF-alpha, which induce a determinant beneficial effect against development of intracellular pathogens; however, sustained production of this cytokine can result in immunopathological diseases. The signals that regulate TNF-alpha production in Vgamma9Vdelta2 T cells are totally unknown. In primary alphabeta T cells, TNF-alpha production was shown to necessitate engagement of the TcR and CD28, and to be independent of the p38 mitogen activated protein kinase pathway. We demonstrate herein that, in contrast to alphabeta T cells, TNF-alpha production in Vgamma9Vdelta2 T lymphocytes is independent of CD28 costimulation and highly dependent on TcR-induced p38 kinase and extracellular signal-regulated kinase 2 pathway activation for optimal cytokine release. Moreover, we bring elements supporting the idea that the "activation threshold" of gammadelta T cells leading to cytokine production is lower than that of alphabeta T cells.

CD28 Antigens↗
PubMed2000

Activation of human Vgamma9Vdelta2 T cells by a Brucella suis non-peptidic fraction impairs bacterial intracellular multiplication in monocytic infected cells.

Human gamma delta T cells are considered to play an important role in the early response to infection with intracellular pathogens. Evidence has been presented that the percentage of gamma delta T cells with Vgamma9Vdelta2 phenotype is dramatically increased in the peripheral blood of patients with acute brucellosis. This specific gd T-cell subpopulation is known to be activated by small non-peptidic molecules that can either be produced by the pathogen itself or released from damaged cells after infection. In the present work we provide evidence that Vgamma9Vdelta2 T lymphocytes from peripheral blood mononuclear cells of healthy donors can be specifically activated by non-peptidic low-molecular-weight compound(s) from Brucella suis lysate. Moreover, we show that Vgamma9Vdelta2 T cells activated by this B. suis fraction produce tumour necrosis factor-alpha and interferon-gamma, which reduce bacterial multiplication inside infected cells.

Antigens, Bacterial↗
PubMed1999

Evidence for a p21(ras)/Raf-1/MEK-1/ERK-2-independent pathway in stimulation of IL-2 gene transcription in human primary T lymphocytes.

T cell stimulation leads to triggering of signals transmitted from the cell membrane to the nucleus through TCR/CD3 proteins. Characterization of these signals largely results from the use of cell lines stimulated with anti-CD3 monoclonal antibodies. These studies have established that activation caused a rapid increase in the formation of GTP-bound Ras, which stimulates the mitogen-activated protein kinase pathway involving the extracellular-regulated kinase-2 (ERK-2) and activates the nuclear factor of activated T cells (NF-AT) that regulates interleukin-2 (IL-2) gene transcription. In the present study, we used human primary T cells, and we investigated the intracellular signals triggered by two different anti-CD3 monoclonal antibodies (UCHT1 and X-35), which both strongly induce cell proliferation. We found that, in contrast to the commonly used UCHT1, X-35 activated IL-2 gene transcription without stimulation of the Raf-1/mitogen-activated ERK kinase-1 (MEK-1)/ERK-2 phosphorylation cascade; we also showed that X-35 stimulation, which triggers an ERK-2-independent pathway, does not involve activation of p21(ras). In addition to demonstrating that activation of p21(ras) and of its Raf-1/MEK-1/ERK-2 effector pathway is not an event obligatorily triggered upon TCR/CD3 ligation, these results provide the first evidence of the existence of a p21(ras)/ERK-2-independent pathway for IL-2 gene transcription in human primary T lymphocytes.

Cells, Cultured↗
PubMed1999

A CD4-independent interaction of human immunodeficiency virus-1 gp120 with CXCR4 induces their cointernalization, cell signaling, and T-cell chemotaxis.

The gp120 envelope glycoprotein of human immunodeficiency virus-1 (HIV-1) interacts with the CXCR4 chemokine receptor, but it is not known whether gp120 activates CXCR4-mediated signaling cascades in the same manner as its natural ligand, SDF1alpha. We assessed the effects of wild-type gp120 and a mutant gp120 that interacts with CXCR4 but not CD4 on CD4(-)/CXCR4(+) cells and CD4(+)/CXCR4(+) cells, respectively. Under both experimental conditions, the interaction of CXCR4 and gp120 resulted in their CD4-independent cointernalization. Both molecules were translocated into early endosomes, whereas neither protein could be detected in late endosomes. Binding of gp120 to CXCR4 resulted in a CD4-independent phosphorylation of Pyk2 and an induction of chemotactic activity, demonstrating that this interaction has functional consequences. Interestingly, however, whereas SDF1alpha activated the ERK/MAP kinase pathway, this cascade was not induced by gp120. Together, these results suggest that the pathology of HIV-1 infection may be modulated by the distinct signal transduction pathway mediated by gp120 upon its interaction with CXCR4.

Antigens, CD↗
PubMed1998

Effector pathways regulating T cell activation.

Activation of T lymphocytes is a key event for an efficient response of the immune system. It requires the involvement of the T cell receptor antigen as well as costimulatory molecules such as CD28. Engagement of these receptors through the interaction with a foreign antigen associated with major histocompatibility complex molecules and CD28 counter-receptors B7.1/B7.2, respectively, results in a series of signaling cascades acting in synergy and which culminate in activation of interleukin-2 gene transcription and eventually cell proliferation. Many studies aimed at characterizing these specific effector pathways have been published; however, the actual signaling molecules that transduce activation signals from the cell membrane to the nucleus and that directly regulate interleukin-2 gene transcription are not yet completely defined and remain a matter of debate. In this commentary, we have attempted to analyze the results, which are sometimes diverging if not totally contradictory, characterizing effector pathways that possibly are triggered during T cell activation.

Animals↗
PubMed1998

The Raf-1/mitogen-activated protein kinase kinase-1/extracellular signal-regulated-2 signaling pathway as prerequisite for interleukin-2 gene transcription in lectin-stimulated human primary T lymphocytes.

It has been shown that stimulation of lymphoid cells causes the activation of the extracellular signal-regulated-2 (ERK-2) which activates nuclear factor of activated T cells (NF-AT), a transcription factor involved in the regulation of interleukin-2 (1L2) gene transcription. ERK-2 is activated via a kinase cascade initiated by activation of the G protein p21Ras followed by phosphorylation and activation of Raf-1 and mitogen-activated protein kinase kinase-1 (MEK-1). Activation of this pathway has been described primarily in human T cell lines; however, using primary T lymphocytes from transgenic mice, a recent study has shown that a blockade of this cascade did not perturb lymphocyte stimulation and proliferation. In the present paper, we studied in human primary T cells the possible involvement of the Raf-1/MEK-1/ERK-2 pathway upon stimulation by jacalin, a mitogenic lectin which specifically stimulates CD4+ lymphocytes. We show here that the mitogen-activated protein (MAP) kinase pathway was stimulated in human purified lymphocytes upon activation with jacalin. Moreover, activation of this pathway appeared to be essential, since its blockade by a specific inhibitor of the MEK-1 kinase abolished IL2 gene transcription; in contrast, in T cells stimulated with phytohemagglutinin M(PHA), another potent T cell mitogenic lectin, blockade of MEK-1 reduced but did not totally inhibit either ERK-2 phosphorylation or IL2 mRNA expression. This shows, as already suggested, that another pathway in addition to the Raf-1/MEK-1/ERK-2 kinase cascade could be triggered in T cell activation. Jacalin stimulation therefore appeared to be a good model for the specific activation of the MAP kinase pathway in human primary T lymphocytes, which would allow the characterisation of drugs specifically targeted to this particular pathway.

Gene Expression Regulation↗
PubMed1997

Transferrin receptor functions as a signal-transduction molecule for its own recycling via increases in the internal Ca2+ concentration.

Transferrin binding to its receptor modulates transferrin receptor (Tf-R) recycling rates in several cells [Klausner, R. D., Van Renswoude, J., Ashwell, G., Kempf, C., Schechter, A., Dean, A. & Bridges, K. R. (1983a) J. Biol. Chem. 258, 4715-4724; Gironès, N. & Davis, R. J. (1989) Biochem. J. 264, 35-46; Sainte-Marie, J., Vidal, M., Bette-Bobillo, P., Philippot, J. R. & Bienvenüe, A. (1991) Eur. J. Biochem. 201, 295-302]. To delineate the mechanism of this regulation, we hypothesized that the binding of the ligand to its receptor could lead to activation of several second-messenger pathways, which may redundantly stimulate recycling of the receptor. The effects of different regulators of Ca2+ flux or concentrations were investigated on the Tf-R-recycling pathway; these studies were carried out in two cell types. Perhexiline, a calcium antagonist, slowed receptor recycling in comparison with the control by more than 80% in L2C cells and by 60% in Jurkat cells (B and T lymphoblasts, respectively) but did not affect their internalization rate. Perhexiline thus trapped considerable amounts of Tf-R in the internal compartment. Ca2+ chelators, such as EGTA or 1,2-bis(2-aminophenoxy)ethane-N,N,N,N'-tetraacetic acid, and a Ca2+-channel inhibitor (Ni2+) decreased drastically the recycling rate of Tf-R. Tf-R recycling was shown to be slowed by a calmodulin antagonist. Conversely, artificial elevation of free internal Ca2+ in L2C cells, using lectin, accelerated the recycling rate. These results suggest that the intracellular Ca2+ concentration plays an important role in the outward flow of transferrin receptors. Consequently, we examined the role of transferrin in internal free Ca2+ regulation. The addition of transferrin or anti-(Tf-R) Ig specifically elicited a rise in [Ca2+], as demonstrated by inefficacy of apotransferrin or irrelevant antibodies. These results suggest that Ca2+ is a regulator of Tf-R recycling and that Tf-R seems to function as a signal-transduction molecule (perhaps in conjunction with other membrane proteins) rather than merely as an endocytic receptor.

Antibodies↗
PubMed1997

The lectin jacalin specifically triggers cell signaling in CD4+ T lymphocytes.

The lectin jacalin was shown to specifically stimulate CD4(+) lymphocytes. This lectin, which presents a peptide highly similar to a sequence of the HIV external glycoprotein, interacts with CD4 and is able to inhibit in vitro HIV infection. Since jacalin binds also CD8, its mitogenic specificity cannot exclusively be attributed to its interaction with CD4. We therefore hypothesized that the lectin could trigger signals specifically associated with CD4. Here we show that jacalin triggers IL2 gene transcription only in CD4(+) lymphocytes. In parallel, we show that numerous proteins are tyrosine phosphorylated in this cell subset while only a restricted number of them are phosphorylated in CD8(+) cells. Moreover, we show that the tyrosine kinase p56lck, which is associated with both CD4 and CD8, is activated only in CD4(+) lymphocytes, making this lectin a good model for the study of cell signaling triggered in this restricted subpopulation.

CD4 Antigens↗
PubMed1997

Evidence for a CD4-associated calcium influx independent of the phosphoinositide transduction pathway in human T cells.

We recently showed, using human Jurkat T cell variants lacking the T cell receptor (TCR)/CD3 complex, that the lectin jacalin is able to trigger intracellular calcium increase provided that CD4 is expressed on the cell surface. Involvement of the CD4 molecule in jacalin-induced biological effects was furthermore demonstrated in differentiated U937 myelomonocytic cells expressing or not expressing CD4, and is confirmed here in human CD4-transfected mouse thymoma cells. In the present paper, we analyze the CD4-associated calcium response triggered by jacalin independently of the TCR/CD3 complex. We show that the observed calcium rise results from a direct long-lasting calcium influx from the outside without release of calcium from intracellular stores. We demonstrate that it is independent of the phosphoinositide phospholipase C transduction pathway. Moreover, we show that this peculiar calcium response can be blocked by protein tyrosine kinase inhibitors (herbimycin and genistein) giving evidence of the involvement of a protein tyrosine kinase, the best candidate of which is the CD4-associated p56lck. Altogether, our results suggest that, independently of the TCR/CD3 complex, CD4 may be involved in the triggering of a calcium signal dependent on a protein tyrosine kinase and independent of the phosphoinositide transduction pathway.

Animals↗
PubMed1996

The lectin jacalin triggers CD4-mediated lymphocyte signaling by binding CD4 through a protein-protein interaction.

The lectin jacalin specifically stimulates lymphocytes expressing the CD4 antigen. Recent studies have also demonstrated that this lectin interacts with CD4, inhibits in vitro HIV infection, and triggers cell signaling directly via CD4. Jacalin as a lectin was suggested to trigger CD4-mediated cell signaling by interacting with the oligosaccharide side chains of CD4 located on Asn271 and Asn3OO. Such a hypothesis was of importance because it implied that the glycosylated chains could represent a functional domain directly involved in CD4-related cell activation. We analyzed this possibility by studying the effect of hapten sugars on jacalin-induced CD4 cell signaling and jacalin/CD4 interaction, and by studying the binding capacities of the lectin toward glycosylated, deglycosylated, and unglycosylated CD4. The results presented in this study provide evidence that jacalin does not recognize the CD4 oligosaccharide chains and actually binds CD4 through a specific protein-protein interaction; as a consequence these results rule out the involvement of the CD4 saccharide moieties in CD4-mediated cell signaling triggered by the lectin.

Base Sequence↗
PubMed1995

Gastrin-CCK-B type receptors on human T lymphoblastoid Jurkat cells.

The presence of specific receptors for gastrointestinal hormones on T cells and their involvement in the immune response are still matters of debate. We reported the effects of gastrin-cholecystokinin (CCK)-related peptides on J.RT3-T3.5 Jurkat cells. A single class of high-affinity binding sites (dissociation constant approximately 0.1 nM) for gastrin and CCK-8 was evident on these cells. These peptides dose-dependently induced a transient increase in intracellular Ca2+ concentration ([Ca2+]i), which was independent of extracellular Ca2-. L-365,260 was 150- to 300-fold more potent than L-364,718 to inhibit radiolabeled ligand binding or peptide-stimulated [Ca2+]i increase, confirming the gastrin-CCK-B nature of the receptor. Gastrin caused a rise in inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] level within 5 s of stimulation. Finally, gastrin increased interleukin (IL)-2 secretion in J.RT3-T3.5 cells. We conclude that 1) J.RT3-T3.5 cells possess "gastrin-CCK-B type" receptors coupled to phospholipase C activation, Ins(1,4,5)P3 formation, and Ca2+ release from intracellular Ca2+ pools, and 2) these receptors could be involved in the regulation of IL-2 production.

Calcium↗
PubMed1994

Involvement of CD4 in interleukin-6 secretion by U937 monocytic cells stimulated with the lectin jacalin.

The lectin jacalin is mitogenic for CD4 expressing T lymphocytes, interacts with the CD4 molecule, and inhibits HIV infection of CD4+ cells. In the present study the effect of jacalin was tested on cells from the monocyte/macrophage lineage that also express the CD4 molecule. We used CD4+ promyelomonocytic U937 cells differentiated towards the monocytic/macrophage lineage with either a mixture of two physiological agents, retinoic acid (RA) and 1 alpha,25-dihydroxyvitamin D3 (VD), or the exogenous drug phorbol myristate acetate (PMA). The cells resulting from these treatments differed in term of CD4 expression. We focused our attention on interleukin-6 (IL-6) production, which implies an activation of the cells differentiated along both pathways. In CD4+ RA/VD-treated cells, jacalin induced a 10-fold higher IL-6 secretion than did lipopolysaccharide (LPS). This jacalin-induced IL-6 production was inhibited by agents interacting with CD4 (anti-CD4 mAbs and HIV recombinant gp120) or by recombinant soluble CD4. In contrast, the CD4- PMA-differentiated U937 cells did not secrete any IL-6 upon jacalin treatment, while they demonstrated a response to LPS similar to that of the RA/VD-differentiated cells. Together with the fact that jacalin interacts with CD4, these results provide evidence of the involvement of a CD4 dependent pathway in IL-6 production.

Antibodies, Monoclonal↗
PubMed1994

Jacalin, a lectin that inhibits in vitro HIV-1 infection, induces intracellular calcium increase via CD4 in cells lacking the CD3/TcR complex.

The lectin jacalin interacts with the CD4 cell surface antigen; this lectin inhibits in vitro infection by human immunodeficiency virus type 1 without preventing virus binding on the host cell. The infection process is known to involve cellular events triggered by the binding of the viral external glycoprotein gp120 to CD4. Herein we demonstrate that jacalin induces cell signaling directly through the CD4 antigen and that independently of the CD3/TcR complex. The capacity of jacalin to trigger cell signals through the CD4 molecule is discussed in relation to its ability to inhibit HIV infection.

CD3 Complex↗
PubMed1993

Inhibition of human immunodeficiency virus infection by the lectin jacalin and by a derived peptide showing a sequence similarity with gp120.

Jacalin is a plant lectin known to specifically induce the proliferation of CD4+ T lymphocytes in human. We demonstrate here that jacalin completely blocks human immunodeficiency virus type 1 (HIV-1) in vitro infection of lymphoid cells. Jacalin does not bind the viral envelope glycoprotein gp120. Besides other T cell surface molecules, it interacts with CD4, the high-affinity receptor to HIV. Binding of jacalin to CD4 does not prevent gp120-CD4 interaction and does not inhibit virus binding and syncytia formation. The anti-HIV effect of the native lectin can be reproduced by its separated alpha-subunits. More importantly, we have defined in the alpha-chain of jacalin a 14-amino acid sequence which shows high similarities with a peptide of the second conserved domain of gp120. A synthetic peptide corresponding to this similar stretch also exerts a potent anti-HIV effect. This peptide is not mitogenic for peripheral blood mononuclear cells and does not inhibit anti-CD3-induced lymphocyte proliferation. These results make jacalin alpha chain-derived peptide a potentially valuable therapeutic agent for acquired immunodeficiency syndrome.

Amino Acid Sequence↗
PubMed1993

The retinoic acid analog CBS-211A potentiates the 1 alpha,25-dihydroxyvitamin D3-induced differentiation of U937 cells.

We report the effect of CBS-211A, a synthetic retinoid analog, designed for topical eye administration, on the growth and differentiation of myelomonocytic cells. This compound was assayed alone or in combination with 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3), since we previously evidenced a synergism of retinoic acid (RA) and 1 alpha,25(OH)2D3 in the induction of U937 cell differentiation. Unlike RA, CBS-211A neither affected the growth of myelomonocytic cells nor differentiated them. Nevertheless, when it was associated with 1 alpha,25(OH)2D3, CBS-211A strongly potentiated the 1 alpha,25(OH)2D3-induced inhibition of U937 cell proliferation and caused a dramatic increase in their differentiation toward monocytes/macrophages. The co-inducing effect of CBS-211A was restricted to U937 cells. Our data suggest that CBS-211A may have therapeutic implications in the treatment of certain kinds of myelomonocytic leukemia. CBS-211A also provides an interesting tool to understand the mechanisms involved in the differentiation of myelomonocytic cells.

Animals↗
PubMed1993

Effect of retinoic acid and vitamin D on the expression of interleukin-1 beta, tumour necrosis factor-alpha and interleukin-6 in the human monocytic cell line U937.

We have previously described a synergism between the two physiological hormones, retinoic acid (RA) and 1 alpha,25-dihydroxyvitamin D3 (VD) in the induction of U937 cell differentiation towards a more mature state. Herein, we investigated the regulation of cytokine production during RA and/or VD treatment of U937 cells. Cell differentiation was followed by measurement of their capacity to give oxidative responses, and interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha) and IL-6 gene and protein expression were determined in RA/VD-treated cells, activated or not with lipopolysaccharide (LPS). The undifferentiated and RA-treated U937 cells were unable to produce monokines even when they were stimulated by LPS. VD induced the monokine mRNA expression in U937 cells but failed to induce protein release. However, unlike RA, it primed the cells to secrete monokines upon endotoxin stimulation. A large enhancement of the production of the monokines both at mRNA and protein levels was observed in the U937 cells exposed to the combination of RA + VD. Nevertheless, protein release required a further step of activation of the RA + VD-primed cells. The co-inducer effect of RA and VD was not observed in HL-60 or THP-1 cells and seems to be restricted to U937 cells. These results on cytokine expression support our previous finding that a combination of RA and VD brings the U937 cells to a high stage of myeloid differentiation with major characteristics of monocytes/macrophages.

Blotting, Northern↗