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PubMed2004

Interferon-gamma is an autocrine mediator for dendritic cell maturation.

Maturation of dendritic cells (DC) is critical for efficient antigen presentation and initiation of an immune response. Interferon-gamma (IFN-gamma) is an important Th1 cytokine. In this study, we investigated the role of IFN-gamma in DC maturation using either IFN-gamma receptor deficient- or IFN-gamma overexpression-models. We showed that immature DC generated in vitro from bone marrow (BM) progenitor cells produced low level of IFN-gamma. After LPS stimulation, DC produced more IFN-gamma, and IFN-gamma productions were at comparable levels among C57BL/6 mice-derived DC (C57BL/6 DC), wild-type 129 mice-derived DC (129 DC) and IFN-gamma receptor deficient 129 mice-derived DC (IFN-gammaR-/-DC). We found that IFN-gammaR-/-DC exhibited decreased expression of CD54, CD86, reduced capacity to secrete IL-1beta and IL-12p70, and impaired capacity to stimulate alloreactive T cells and to drive Th1 differentiation. Transfection of IFN-gamma gene into DC promoted DC to express higher CD40, CD54, CD80, CD86, CCR7 and I-Ab, secrete more IL-1beta and IL-12p70, and more potently activate both CD4 and CD8 T cells. These data suggest that IFN-gamma signaling pathway is important for the maturation of DC in an autocrine fashion.

Animals↗
PubMed2006

The autocrine motility factor (AMF) and AMF-receptor combination needs sugar chain recognition ability and interaction using the C-terminal region of AMF.

The autocrine motility factor (AMF) promotes cellular locomotion or invasion, and regulates tumor angiogenesis or ascites accumulation. These signals are triggered by binding between AMF and its receptor (AMFR), a glycoprotein on the cell surface. AMF has been identified as phosphohexose isomerase (PHI). Previous reports have suggested that the substrate-recognition of exo-PHI is significant for receptor binding. Crystallographic studies have shown that AMF consists of three domains, and that the substrate or inhibitor of PHI is stored between the large and small domains, corresponding to approximately residues 117-288. Here, site-directed mutagenesis was used to investigate 18 recombinant human AMF point mutants involving critical amino acid residues for substrate or enzyme inhibitor recognition or binding. Mutation of residues that interact with the phosphate group of the PHI substrate significantly reduced the cell motility-stimulating activity. Their binding capacities for AMFR were also lower than wild-type human AMF. Mutants that retained the enzymic activity showed the motility-stimulating effect and receptor binding and had sensitivity to a PHI inhibitor. Mutant AMFR lacking the N-sugar chain was expressed on the cell membrane but did not respond to AMF-stimulation, and N-glycosidase-treated AMFR did not compete with receptor binding of AMF. Furthermore, the AMF domains that contain the substrate storage domain and C-terminal region stimulate cell locomotion. These results suggest that the N-glyco side-chain of AMFR is a trigger and that interaction between the 117-C-terminal part of AMF and the extracellular core protein of AMFR is needed during AMF-AMFR interactions.

Cell Line, Tumor↗
PubMed2004

Autocrine actions of macrophage-derived catecholamines on interleukin-1 beta.

Previous studies indicate that norepinephrine and epinephrine modulate production of interleukin-1(beta) (IL-1(beta)) by activated macrophages, but it is not known if macrophage-derived catecholamines affect IL-1(beta). In this study, recruited peritoneal macrophages from CBA/J female mice were activated with lipopolysaccharide (LPS) and treated with vehicle or adrenergic receptor antagonists for 24 h. Extracellular and intracellular levels of IL-1(beta) were measured with ELISA. Treatment with the beta-adrenergic receptor antagonists propranolol or ICI 118,551 increased LPS-induced production of IL-1(beta), whereas treatment with the alpha-adrenergic antagonists phentolamine or yohimbine decreased IL-1(beta). These findings demonstrate that adrenergic receptor antagonists unmask autocrine actions of macrophage-derived catecholamines on IL-1(beta) that may influence the inflammatory response.

Adjuvants, Immunologic↗
PubMed2004

Stem cell factor and c-kit are expressed by and may affect vascular SMCs through an autocrine pathway.

INTRODUCTION: Stem cell factor (SCF) is a membrane-bound and soluble growth factor that activates the c-kit tyrosine kinase receptor. Given the similarities between c-kit and platelet-derived growth factor (PDGF) receptors, we hypothesized that similar to PDGF, SCF/c-kit signaling may play a role in smooth muscle cell (SMC) function and thus the development of intimal hyperplasia. MATERIALS AND METHODS: Human saphenous vein SMCs were harvested from veins procured at the time of bypass grafting. Carotid arteries from rats that were balloon injured (n = 12) at variable time points were compared to sham-operated controls (n = 3). Expression of SCF and c-kit was measured by immunohistochemistry (IHC) and Western blotting. RESULTS: Western blotting revealed that human SMCs express membrane-bound SCF. In separate experiments, we found that this growth factor undergoes proteolytic cleavage to its soluble form following exposure to matrix metalloproteinase-9 (MMP-9), a ubiquitous MMP released at the time of arterial injury. We next evaluated in human SMCs, expression of the SCF receptor, c-kit. Western blotting of human SMC lysates revealed minor but consistent expression of c-kit. IHC demonstrated c-kit expression to be localized to the media. To determine if c-kit is up-regulated during the development of intimal hyperplasia, we evaluated expression of this receptor in a rat carotid balloon injury model. Quantification of IHC staining on injured vessels revealed that c-kit expression within the media was significantly increased at 3, 7, 14, and 28 days following injury (28.1, 30.8, 16, and 10.4% increase over sham controls, respectively, P < 0.05). Furthermore, c-kit expression was prominent within the neointima and maximal at 7 days (53.4 +/- 7.8% of area c-kit positive). CONCLUSION: Human vascular SMCs express the growth factor SCF and its receptor, c-kit. SCF is released from its membrane-bound form via MMP-9. This finding and the dramatic increase in c-kit expression observed in the rat carotid artery after balloon injury suggests SCF/c-kit signaling may affect SMC function via an autocrine pathway.

Animals↗
PubMed2004

Autocrine regulation of steroidogenic function of Leydig cells by transforming growth factor-alpha.

We have determined the effects of LH on the expression of transforming growth factor-alpha (TGFalpha) and epidermal growth factor receptor (EGFR) system in rat Leydig cells and investigated its role in steroidogenesis. LH and TGFalpha/epidermal growth factor (EGF) significantly increased the levels of TGFalpha mRNA and protein, and the levels of EGFR protein in immature rat Leydig cells (ILC). Treatment with TGFalpha or EGF for 24h resulted in significant increase in androgen production in ILC. The increase in androgen production in response to TGFalpha was associated with increased mRNA levels of SR-BI, steroidogenic acute regulatory (StAR) and P450scc but not of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and P450c17. TGFalpha also caused a marked increase in the levels StAR protein in ILC. EGFR inhibitor (AG1478) blocked the effects of TGFalpha while MEK-inhibitor (PD98059) potentiated TGFalpha or LH effects on steroidogenesis. A PKA inhibitor (H89) blocked both TGFalpha and LH effects on steroidogenesis. We conclude that TGFalpha plays an autocrine role in LH dependent development and function of Leydig cells.

Androgens↗
PubMed2004

The trunk neural crest and its early glial derivatives: a study of survival responses, developmental schedules and autocrine mechanisms.

Regulation of survival during gliogenesis from the trunk neural crest is poorly understood. Using adapted survival assays, we directly compared crest cells and the crest-derived precursor populations that generate satellite cells and Schwann cells. A range of factors that supports Schwann cells and glial precursors does not rescue crest, with the major exception of neuregulin-1 that rescues crest cells provided they contact the extracellular matrix. Autocrine survival appears earlier in developing satellite cells than Schwann cells. Satellite cells also show early expression of S100beta, BFABP and fibronectin and early survival responses to IGF-1, NT-3 and PDGF-BB that in developing Schwann cells are not seen until the precursor/Schwann cell transition. These experiments define novel differences between crest cells and early glia and show that entry to the glial lineage is an important point for regulation of survival responses. They show that survival mechanisms among PNS glia differ early in development and that satellite cell development runs ahead of schedule compared to Schwann cells in several significant features.

Animals↗
PubMed2004

JNK regulates autocrine expression of TGF-beta1.

The c-Jun NH2-terminal kinase (JNK) has been implicated in the function of transforming growth factor beta (TGF-beta). To test the role of JNK, we examined the effect of compound disruption of the murine genes that encode the ubiquitously expressed isoforms of JNK (Jnk1 and Jnk2). We report that JNK-deficient fibroblasts isolated from Jnk1-/- Jnk2-/- mice constitutively express TGF-beta1. Complementation studies demonstrate that JNK is a repressor of Tgf-beta1 gene expression. This mechanism of regulation of TGF-beta1 expression by JNK represents an unexpected form of cross-talk between two important signaling pathways. Together, these data demonstrate that the JNK pathway may contribute to the regulation of autocrine TGF-beta1-mediated biological responses in vivo.

Activin Receptors, Type I↗
PubMed2005

Pigment epithelium-derived factor (PEDF) promotes growth of pericytes through autocrine production of platelet-derived growth factor-B.

Microvessels are composed of two types of cells, endothelial cells and pericytes. Pericyte loss or dysfunction participates in various types of disorders, including diabetic retinopathy. Recently, decreased levels of pigment epithelium-derived factor (PEDF) in the eye have been found to predict progression of diabetic retinopathy. However, the effect of PEDF on pericyte growth remains to be unknown. In this study, we investigated whether or how PEDF could stimulate proliferation of cultured retinal pericytes. PEDF stimulated DNA synthesis in pericytes in a dose-dependent manner. PEDF up-regulated pericyte mRNA levels of platelet-derived growth factor-B (PDGF-B). Down-regulation of PDGF-B gene expression by small interfering RNAs completely inhibited the PEDF-induced DNA synthesis in pericytes. Furthermore, PEDF increased protein kinase C (PKC) activity in pericytes and staurosporine, a potent cell-permeable inhibitor of PKC, completely blocked the PDGF-B gene induction and subsequent increase in DNA synthesis in PEDF-exposed pericytes. These results demonstrate that PEDF promotes the growth of cultured pericytes possibly through autocrine production of PDGF-B via PKC activation. Our present study suggests that PEDF could act as a mitogen or survival factor for pericytes, thereby being involved in the maintenance of retinal microvascular homeostasis.

Animals↗
PubMed2004

Serotonin regulates the secretion and autocrine action of a neuropeptide to activate MAPK required for long-term facilitation in Aplysia.

In Aplysia, long-term facilitation (LTF) of sensory neuron synapses requires activation of both protein kinase A (PKA) and mitogen-activated protein kinase (MAPK). We find that 5-HT through activation of PKA regulates secretion of the sensory neuron-specific neuropeptide sensorin, which binds autoreceptors to activate MAPK. Anti-sensorin antibody blocked LTF and MAPK activation produced by 5-HT and LTF produced by medium containing sensorin that was secreted from sensory neurons after 5-HT treatment. A single application of 5-HT followed by a 2 hr incubation with sensorin produced protein synthesis-dependent LTF, growth of new presynaptic varicosities, and activation of MAPK and its translocation into sensory neuron nuclei. Inhibiting PKA during 5-HT applications and inhibiting receptor tyrosine kinase or MAPK during sensorin application blocked both LTF and MAPK activation and translocation. Thus, long-term synaptic plasticity is produced when stimuli activate kinases in a specific sequence by regulating the secretion and autocrine action of a neuropeptide.

Amino Acid Sequence↗
PubMed2004

Autocrine and paracrine actions of natriuretic peptides in the heart.

The natriuretic peptides, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), are a family of polypeptide mediators exerting numerous actions in cardiovascular homeostasis. ANP and BNP are cardiac derived, being secreted and up-regulated in myocardium in response to many pathophysiological stimuli. CNP is an endothelium-derived mediator. The classical endocrine effects of ANP and BNP on fluid homeostasis and blood pressure, especially in conditions characterised by left ventricular dysfunction, are well recognised and extensively researched. However, there is accumulating evidence that, in addition to endocrine actions, ANP and BNP exhibit important autocrine and paracrine functions within the heart and coronary circulation. These include regulation of myocyte growth, inhibition of fibroblast proliferation and extracellular matrix deposition, a cytoprotective anti-ischaemic (preconditioning-like) function, and influences on coronary endothelium and vascular smooth muscle proliferation and contractility. Most if not all of these actions can be ascribed to particulate guanylyl cyclase activation because the ANP/BNP receptor, natriuretic peptide receptor (NPR)-A, has an intracellular guanylyl cyclase domain. Subsequent elevation of the intracellular second messenger cGMP may exert diverse physiological effects through activation of cGMP-dependent protein kinases (cGK), predominantly cGK-I. However, there appear to be other contributory mechanisms in several of these actions, including the augmentation of nitric oxide synthesis. These diverse actions may represent counterregulatory mechanisms in the pathophysiology of many cardiovascular diseases, not just those typified by left ventricular dysfunction. Ultimately, insights from the autocrine/paracrine actions of natriuretic peptides may provide routes to therapeutic application in cardiac diseases of natriuretic peptides and drugs that modify their availability.

Animals↗
PubMed2006

Evidence that autocrine signaling through Bmpr1a regulates the proliferation, survival and morphogenetic behavior of distal lung epithelial cells.

Lung development requires reciprocal epithelial/mesenchymal interactions, mediated by signaling factors such as Bmps made in both cell populations. To address the role of Bmp signaling in the epithelium, we have exploited the fact that Bmp receptor type Ia (Alk3) is expressed in the epithelium during branching morphogenesis. Deletion of Bmpr1a in the epithelium with an Sftpc-cre transgene leads to dramatic defects in lung development. There is reduced epithelial proliferation, extensive apoptosis, changes in cell morphology and extrusion of cells into the lumen. By E18.5, there are fewer Type II cells than normal, and the lung contains large fluid-filled spaces. If cell death is prevented by making embryos homozygous null for the proapoptotic gene, Bax, the epithelial cells that are rescued can apparently differentiate, but normal morphogenesis is not restored. To determine whether Bmps made by the epithelium can function in an autocrine manner, mesenchyme-free endoderm was cultured in Matrigel with Fgfs. Under these conditions, the mutant epithelium fails to undergo secondary budding. Abnormal development was also seen when Bmp4 was specifically deleted in the epithelium using the Sftpc-cre transgene. Our results support a model in which Bmp signaling primarily regulates the proliferation, survival and morphogenetic behavior of distal lung epithelial cells.

Animals↗
PubMed2006

Autocrine production of TGF-beta confers resistance to apoptosis after an epithelial-mesenchymal transition process in hepatocytes: Role of EGF receptor ligands.

Transforming growth factor-beta (TGF-beta) induces apoptosis in fetal rat hepatocytes. However, a subpopulation of these cells survives, concomitant with changes in phenotype, reminiscent of an epithelial-mesenchymal transition (EMT). We have previously suggested that EMT might confer cell resistance to apoptosis (Valdés et al., Mol. Cancer Res., 1: 68-78, 2002). However, the molecular mechanisms responsible for this resistance are not explored yet. In this work, we have isolated and subcultured the population of hepatocytes that suffered the EMT process and are resistant to apoptosis (TGF-beta-treated fetal hepatocytes: TbetaT-FH). We prove that they secrete mitogenic and survival factors, as analyzed by the proliferative and survival capacity of conditioned medium. Inhibition of the epidermal growth factor receptor (EGFR) sensitizes TbetaT-FH to die after serum withdrawal. TbetaT-FH expresses high levels of transforming growth factor-alpha (TGF-alpha) and heparin-binding EGF-like growth factor (HB-EGF) and shows constitutive activation of the EGFR pathway. A blocking anti-TGF-alpha antibody restores the capacity of cells to die. TGF-beta, which is expressed by TbetaT-FH, mediates up-regulation of TGF-alpha and HB-EGF expression in those cells. In summary, results suggest that an autocrine loop of TGF-beta confers resistance to apoptosis after an EMT process in hepatocytes, through the increase in the expression of EGFR ligands.

Animals↗
PubMed2006

An autocrine role for leptin in mediating the cardiomyocyte hypertrophic effects of angiotensin II and endothelin-1.

Leptin is a 16 kDa product of the obesity gene secreted primarily by adipocytes. We recently identified cardiomyocytes as a target for the direct hypertrophic effects of leptin and suggested that leptin may be a biological link between obesity and cardiovascular pathologies. Activation of the renin-angiotensin and endothelin systems is associated with development of cardiovascular diseases and plasma renin levels are elevated in obese individuals. We therefore determined possible interaction between these factors in mediating hypertrophy in cultured neonatal rat ventricular myocytes. Treatment for 24 h with leptin (3.1 nM), angiotensin II (100 nM) or endothelin-1 (ET-1, 10 nM) significantly increased cell area by 37%, 36% and 35%, respectively and significantly increased gene expression of myosin light chain-2 and alpha-skeletal actin as well as leucine incorporation. The hypertrophic effects of all three agents were prevented by leptin and a leptin triple mutant receptor antagonist whereas the AT(1) receptor blocker (Sar1-lle(8))-Ang II or the ET(A) receptor blocker BQ123 was ineffective against leptin-induced hypertrophy. Both angiotensin II and ET-1 significantly increased leptin levels in the culture medium by fivefold. Moreover, both angiotensin II and ET-1 increased the gene expression of the short form (OBRa) by 180% and long form (OBRb) of leptin receptors by 200%, and this increase was abolished by both leptin receptor and leptin antibodies and leptin triple mutant. Although both angiotensin II and ET-1 increased phosphorylation of MAPK (p38, ERK1/2 and JNK) and NF-kappaB, the ability of leptin blockade to attenuate the hypertrophic responses was generally dissociated from these effects suggesting an alternate, yet to be identified cellular pathway mediating this role of leptin. Our studies therefore suggest a novel autocrine function for leptin in mediating the hypertrophic effects of both angiotensin II and ET-1 in cardiac myocytes.

Adipocytes↗
PubMed2003

Regulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and angiogenesis by an insulin-like growth factor-I receptor autocrine loop in human pancreatic cancer.

Activation of the insulin-like growth factor-I receptor (IGF-IR) was recently shown to modulate angiogenesis by up-regulating the expression of vascular endothelial growth factor (VEGF). We hypothesized that inhibiting IGF-IR function would inhibit angiogenesis and growth of pancreatic cancer in vivo and sought to identify major signaling pathways regulated by IGF-IR in pancreatic cancer cells. Human pancreatic cancer cells (L3.6pl) were stably transfected with a dominant-negative form of IGF-IR (IGF-IR DN) or an empty vector (pcDNA). In vitro, IGF-IR DN cells exhibited a decrease in both constitutive and inducible phosphorylation of IGF-IR and Erk1/2. Constitutive expression of nuclear hypoxia-inducible factor-1alpha and secreted VEGF (P < 0.01) protein levels also were significantly lower in IGF-IR DN cells than in pcDNA cells. In vivo, IGF-IR inhibition led to decreases in pancreatic tumor volume and weight, vessel density, and tumor cell proliferation (P < 0.01 for all) and increases in tumor cell apoptosis (P < 0.02). Our results suggest that autocrine activation of the IGF-IR system significantly affects VEGF expression and angiogenesis in human pancreatic cancer. Thus, IGF-IR may be a valid target in the treatment of pancreatic cancer.

Adenocarcinoma↗
PubMed2000

Keloid-derived fibroblasts are refractory to Fas-mediated apoptosis and neutralization of autocrine transforming growth factor-beta1 can abrogate this resistance.

The pathogenesis of keloid remains poorly understood. As no effective therapy for keloid is as yet available, an insight into its pathogenesis may lead to novel approaches. Apoptosis has been found to mediate the decrease in cellularity during the transition between granulation tissue and scar. Here, we report that in contrast to hypertrophic scar-derived and normal skin-derived fibroblasts, keloid-derived fibroblasts are significantly resistant to both Fas-mediated and staurosporine-induced apoptosis. The caspases-3, -8, and -9 were not activated indicating that the block in the apoptotic pathway in keloid is upstream of the caspases. There were no significant differences in the level of expression of Fas, Bcl-2, and Bax between the three groups but addition of transforming growth factor (TGF)-beta1 significantly inhibited Fas-mediated apoptosis in hypertrophic scar-derived and normal skin-derived fibroblasts and neutralization of autocrine TGF-beta1 with anti-TGF-beta1 antibody abrogated the resistance of keloid-derived fibroblasts. Anti-apoptotic activity was not observed with TGF-beta2. This is the first study linking refractory Fas-mediated apoptosis to cellular phenotype in keloids and indicating a pivotal role for the anti-apoptotic effect of TGF-beta1 in this resistance. Hence, it becomes important to treat keloids as a separate entity different from hypertrophic scars and enhancement of Fas-sensitivity could be a promising therapeutic target.

Antibodies↗
PubMed2001

Autocrine motility factor receptor expression in patients with stage I non-small cell lung cancer.

BACKGROUND: Expression of autocrine motility factor receptor (AMFR) associates with increased cell migration and poor survival in certain types of human cancers. We assessed the possible correlation between AMFR, clinicopathologic features, and survival in stage I non-small cell lung cancer (NSCLC). METHODS: AMFR expression was analyzed immunohistochemically, using a monoclonal antibody (3F3A) in tumor specimens from 97 patients with curative resection. Vascular endothelial growth factor (VEGF) expression was also examined after accounting for AMFR expression. RESULTS: Out of 97 tumors, 38 (39.2%) were positively stained with AMFR. The AMFR expression was significantly associated with histologic type of tumor, mainly in adenocarcinoma. Overall survival of patients with AMFR-positive tumors was significantly worse than that of AMFR-negative tumors (p = 0.0050). The AMFR expression appears to be associated with VEGF expression. Patients who were AMFR positive and had high VEGF expression had a worse prognosis compared with the AMFR-negative and low VEGF-expression group (p < 0.0001). Multivariate analysis revealed an independent prognostic impact of AMFR on survival (p = 0.0039). CONCLUSIONS: These results indicate that evaluation of AMFR expression may provide useful guidance in follow-up of patients with NSCLC.

Aged↗
PubMed2002

Tumor autocrine motility factor induces hyperpermeability of endothelial and mesothelial cells leading to accumulation of ascites fluid.

Accumulation of ascites fluid often observed in some solid tumors is one of the most devastating conditions of a patient's difficulty in responding to treatment, and to a decrease in the quality of life. Various factors are thought to be associated with the formation of cancer-induced fluid accumulation and hyperpermeability of a blood vessel is thought to go with this process. Here, we report a new factor that is involved in this process, e.g., autocrine motility factor (AMF). AMF is a tumor-related cytokine which stimulates the tumor cell locomotion and migration and promotes tumor cell invasion during metastasis. AMF secretion and its receptor (AMFR) expression in tumor cells are closely correlated with disease aggravation of convalescence. The response of endothelial or mesothelial cellular morphological alternation to AMF leads to motile enhancement and vascular permeability. Tumor AMF induces gaps in an endothelial or mesothelial monolayer by stimulating a cellular movement, and accelerates the ascites accumulation. And treatment experiment with anti-AMF antibody succeeded in the reduction of the ascites accumulation, which renders AMF to the target molecule. It is suggested that AMF is one of the significant factors which relates to various pathological malignancies induced by tumor mass, and understanding of its function could benefit prognosis and treatment.

Animals↗
PubMed2001

NO as an autocrine mediator in the apoptosis of activated microglial cells: correlation between activation and apoptosis of microglial cells.

Abnormal activation of microglial cells has been implicated in various neurodegenerative diseases. Microglial activation needs to be tightly regulated for physiological maintenance and normal functioning of the central nervous system. Potential mechanisms for the down-regulation of activated microglial cells are the deactivation or elimination of activated cells. We hypothesized that the elimination of activated microglial cells by apoptosis is one of the key mechanisms of auto-regulation of activated microglial cells. To test this hypothesis, we utilized BV-2 mouse microglial cells and rat primary microglial cultures exposed to activating agents such as lipopolysaccharide and interferon-gamma, and investigated a possible correlation between apoptosis and activation of these cells. We found that the activation of microglial cells led to apoptotic death, and the activation state of microglial cells inversely correlated with cell viability. We have also demonstrated that: (i) NO was produced by activated microglial cells in a manner dependent on time and dose of activating agents; (ii) inhibition of NO synthesis by iNOS inhibitor blocked the apoptosis of activated microglial cells; (iii) an exogenous NO donor induced apoptosis of microglial cells; and (iv) inhibition of TNFalpha or FasL using neutralizing antibodies did not affect activation-induced apoptosis of microglial cells. These results indicated that activation of microglial cells leads to the production of NO, which in turn acts as the major mediator of cellular apoptosis in an autocrine fashion. Our work suggests the presence of auto-regulatory mechanism for microglial activation, which may have relevance in the pathogenesis of various neurodegenerative diseases possibly resulting from 'over-activation' of microglial cells.

Animals↗