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Autocrine Loop (autocrine + loop)

Distribution by Scientific Domains

Medical Sciences	80%

Selected Abstracts

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2005
Ingrid
Abstract Dendritic cells (DC) are key components of innate and adaptive immune responses. Plasmacytoid DC (PDC) are a specialized DC subset that produce high amounts of type I interferons in response to microbes. High mobility group box 1 protein (HMGB1) is an abundant nuclear protein, which acts as a potent pro-inflammatory factor when released extracellularly. We show that HMGB1 leaves the nucleus of maturing PDC following TLR9 activation, and that PDC express on the plasma membrane the best-characterized receptor for HMGB1, RAGE. Maturation and type I IFN secretion of PDC is hindered when the HMGB1/RAGE pathway is disrupted. These results reveal HMGB1 and RAGE as the first known autocrine loop modulating the maturation of PDC, and suggest that antagonists of HMGB1/RAGE might have therapeutic potential for the treatment of systemic human diseases. [source]

The core-aldehyde 9-oxononanoyl cholesterol increases the level of transforming growth factor ,1-specific receptors on promonocytic U937 cell membranes

AGING CELL, Issue 2 2009
Simona Gargiulo
Summary Among the broad variety of compounds generated via oxidative reactions in low-density lipoproteins (LDL) and subsequently found in the atherosclerotic plaque are aldehydes that are still esterified to the parent lipid, termed core aldehydes. The most represented cholesterol core aldehyde in LDL is 9-oxononanoyl cholesterol (9-ONC), an oxidation product of cholesteryl linoleate. 9-ONC, at a concentration detectable in biological material, markedly up-regulates mRNA expression and protein level of both the pro-fibrogenic and pro-apoptotic cytokine transforming growth factor ,1 (TGF-,1) and the TGF-, receptor type I (T,RI) in human U937 promonocytic cells. We also observed increased membrane presentation of TGF-, receptor type II (T,RII). Experiments employing the T,RI inhibitor SB431542, or the TGF, antagonist DANFc chimera, have shown that the effect on T,RI is directly induced by 9-ONC, while T,RII up-regulation seems stimulated by its specific ligand, i.e. TGF,1, over-secreted meanwhile by treated cells. Increased levels of the cytokine and of its specific receptors in 9-ONC-treated cells clearly occurs through stimulation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), as demonstrated by ERK1/2 knockdown experiments using mitogen-activated protein kinase/extracellular signal-regulated kinase 1 and 2 (MEK1 and MEK2) siRNAs, or PD98059, a selective MEK1/2 inhibitor. 9-ONC might thus sustain further vascular remodeling due to atherosclerosis, not simply by stimulating synthesis of the pro-fibrogenic cytokine TGF-,1 in vascular cells, but also and chiefly by enhancing the TGF-,1 autocrine loop, because of the marked up-regulation of the cytokine's specific receptors T,RI and T,RII. [source]

PKC-mediated secretion of death factors in LNCaP prostate cancer cells is regulated by androgens

MOLECULAR CARCINOGENESIS, Issue 3 2009
Liqing Xiao
Abstract Activation of PKC, in androgen-dependent LNCaP prostate cancer cells leads to apoptosis via the activation of p38 MAPK and JNK cascades. We have recently shown that treatment of LNCaP cells with phorbol 12-myristate 13-acetate (PMA) leads to a PKC,-mediated autocrine release of death factors, including the cytokines TNF, and TRAIL, and that conditioned medium (CM) collected from PMA-treated LNCaP cells promotes the activation of the extrinsic apoptotic cascade. Interfering with this autocrine loop either at the level of factor release or death receptor activation/signaling markedly impaired the PMA apoptotic response. In the present study we show that this PKC,-dependent autocrine mechanism is greatly influenced by androgens. Indeed, upon androgen depletion, which down-regulates PKC, expression, TNF, and TRAIL mRNA induction and release by PMA are significantly diminished, resulting in a reduced apoptogenic activity of the CM and an impaired ability of the CM to activate p38 MAPK and JNK. These effects can be rescued by addition of the synthetic androgen R1881. Furthermore, RNAi depletion of the androgen-receptor (AR) from LNCaP cells equally impaired PMA responses, suggesting that PKC-mediated induction of death factor secretion and apoptosis in LNCaP prostate cancer cells are highly sensitive to hormonal control. © 2008 Wiley-Liss, Inc. [source]

HLA,B27,restricted antigen presentation by human chondrocytes to CD8+ T cells: Potential contribution to local immunopathologic processes in ankylosing spondylitis

ARTHRITIS & RHEUMATISM, Issue 6 2009
Maren Kuhne
Objective Analysis of the histopathologic features of hip arthritis in patients with ankylosing spondylitis (AS) has revealed accumulation of infiltrating mononuclear cells in the bone end plate and presence of hyaline articular cartilage that is not found in areas of total cartilage destruction. This study was undertaken to assess whether chondrocytes attract lymphocytes and whether cartilage chondrocytes from patients with AS have the potential to directly stimulate T cells in an HLA-restricted manner. Methods Human HLA,B27+ T cell lines, specific for the Epstein-Barr virus,derived peptide EBNA258,266, and autologous chondrocytes, serving as nonprofessional antigen-presenting cells (APCs), were available for use in a model system to study chondrocyte functions in femoral head joint cartilage of patients with AS. Peptide functionality of cytotoxic T cells was assessed by flow cytometry, and cellular interactions were detected by fluorescence confocal microscopy. Results When maintained in an alginate matrix, chondrocytes isolated from the femoral heads of patients with AS constitutively expressed type II collagen and CD80. When pulsed with the EBNA258,266 peptide, autologous chondrocytes functioned as APCs and, specifically, induced interferon-, production in CD8+ T cells. In mixed chondrocyte,T cell cultures, cell,cell contacts were dependent on the presence of the EBNA258,266 peptide. T cells adjacent to chondrocytes produced perforin and granzyme B; both molecules were found in focal aggregates, a prerequisite for antigen-specific lysis of target cells. Conclusion Antigen presentation through human chondrocytes allows the stimulation of peptide-specific CD8+ T cells. These results indicate that human chondrocytes can act as nonprofessional APCs, and suggest that there is an interferon-,,triggered autocrine loop of immune cell,mediated chondrocyte activation in the already inflamed environment. Thus, local HLA-dependent activation of peptide-specific cytotoxic CD8+ T cells by chondrocytes might contribute to inflammatory processes in the spondylarthritides. [source]

Angiogenesis: now and then,

APMIS, Issue 7-8 2004
CARLA COSTA
Angiogenesis or new blood vessel formation plays an essential role during embryogenesis, adult vascular remodeling and in several pathological disorders, as in tumor development. Although sprouting of blood vessels is the principal angiogenic mechanism, additional ones, such as the recruitment of bone marrow-derived cells, have recently been described. These processes are controlled by several molecules, although members of the VEGF family of angiogenic factors and its receptors seem to be the main mediators. Initially, VEGF receptors were described as endothelial specific; however, further studies have reported their presence in several types of cells of non-endothelial origin, such as tumor cells. This VEGF receptor altered expression has suggested an angiogenesis-independent growth advantage mechanism on certain types of cancers by the generation of autocrine loops. A possible role in tumorigenesis and a potential novel target in cancer therapy have been hypothesized. Detection of other receptors and molecules considered to be angiogenic players has also been observed on tumor cells. Currently, their clinical significance as well as their potential as therapeutic targets for the treatment of certain cancers is being evaluated, having in mind the future development of promising mechanism-based therapies. The aspects mentioned above are the main focus of this review, which aims to throw light on recent findings respecting angiogenesis and novel therapeutic approaches. [source]