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Proinflammatory Molecules (proinflammatory + molecule)
Selected AbstractsCannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: Relevance for Huntington's diseaseGLIA, Issue 11 2009Onintza Sagredo Abstract Cannabinoid agonists might serve as neuroprotective agents in neurodegenerative disorders. Here, we examined this hypothesis in a rat model of Huntington's disease (HD) generated by intrastriatal injection of the mitochondrial complex II inhibitor malonate. Our results showed that only compounds able to activate CB2 receptors were capable of protecting striatal projection neurons from malonate-induced death. That CB2 receptor agonists are neuroprotective was confirmed by using the selective CB2 receptor antagonist, SR144528, and by the observation that mice deficient in CB2 receptor were more sensitive to malonate than wild-type animals. CB2 receptors are scarce in the striatum in healthy conditions, but they are markedly upregulated after the lesion with malonate. Studies of double immunostaining revealed a significant presence of CB2 receptors in cells labeled with the marker of reactive microglia OX-42, and also in cells labeled with GFAP (a marker of astrocytes). We further showed that the activation of CB2 receptors significantly reduced the levels of tumor necrosis factor-, (TNF-,) that had been increased by the lesion with malonate. In summary, our results demonstrate that stimulation of CB2 receptors protect the striatum against malonate toxicity, likely through a mechanism involving glial cells, in particular reactive microglial cells in which CB2 receptors would be upregulated in response to the lesion. Activation of these receptors would reduce the generation of proinflammatory molecules like TNF-,. Altogether, our results support the hypothesis that CB2 receptors could constitute a therapeutic target to slowdown neurodegeneration in HD. © 2008 Wiley-Liss, Inc. [source] Inflammation: A new candidate in modulating adult neurogenesisJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2008Sulagna Das Abstract Any pathological perturbation to the brain provokes a cascade of molecular and cellular events, which manifests in the form of microglial activation and release of various proinflammatory molecules. This eventually culminates in a profound neuroinflammatory reaction that characterizes the brain's response to stress, injury, or infection. The inflammatory cascade is an attempt by the system to eliminate the challenge imposed on the brain, clear the system of the dead and damaged neurons, and rescue the normal functioning of this vital organ. However, during the process of microglial activation, the proinflammatory mediators released exert certain detrimental effects, and neural stem cells and progenitor cells are likely to be affected. Here we review how the proliferation, maturation, and migration of the neural stem cells are modulated under such an inflammatory condition. The fate of the noncommitted neural stem cells and its differentiation potency are often under strict regulation, and these proinflammatory mediators seem to disrupt this critical balance and finely tune the neurogenesis pattern in the two niches of neurogenesis, the subventricular zone and the subgranular zone of the hippocampus. Moreover, the migration ability of these stem cells, which is important for localization to the proper site, is also affected in a major way by the chemokines released following inflammation. © 2007 Wiley-Liss, Inc. [source] IL-1,, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NF-,B pathwaysJOURNAL OF NEUROSCIENCE RESEARCH, Issue 5 2006Yun-Jung Kim Abstract In the present study we sought to examine cell,cell interactions by investigating the effects of factors released by stimulated microglia on inducible nitric oxide (NO) synthase (iNOS) induction in astrocytoma cells. After examining the temporal profiles of proinflammatory molecules induced by lipopolysaccharide (LPS) stimulation in BV2 microglial cells, iNOS and IL-1, were observed to be the first immediate-response molecules. Removal of LPS after 3 hr stimulation abrogated NO release, whereas a full induction of IL-1, was retained in BV2 cells. We observed consistently that conditioned medium (CM) from activated microglia resulted in the induction of iNOS in C6 cells, and IL-1, was shown to be a key regulator of iNOS induction. An IL-1,-neutralizing antibody diminished NO induction. Incubation with recombinant IL-1, stimulated NO release to a lesser extent compared to microglial CM; co-treatment of LPS and IL-1, had a potent, synergistic effect on NO release from C6 cells. Transient transfection with MEK kinase 1 (MEKK1) or nuclear factor-kappa B (NF-,B) expression plasmids induced iNOS, and IL-1, further enhanced the MEKK1 response. Furthermore, IL-1,-mediated NO release from C6 cells was significantly suppressed by inhibition of p38 mitogen activated protein kinase (MAPK) or NF-,B by specific chemical inhibitors. Both IL-1, and MEKK1 stimulated p38 and JNK MAPKs, as well as the NF-,B pathway, to induce iNOS in C6 cells. Microglia may represent an anti-tumor response in the central nervous system, which is potentiated by the local secretion of immunomodulatory factors that in turn affects astrocytoma (glioma) cells. A better understanding of microglia,glioma or microglia,astrocyte interactions will help in the design of novel immune-based therapies for brain tumors or neuronal diseases. © 2006 Wiley-Liss, Inc. [source] Functional characterization of TRPV4 as an osmotically sensitive ion channel in porcine articular chondrocytesARTHRITIS & RHEUMATISM, Issue 10 2009Mimi N. Phan Objective Transient receptor potential vanilloid 4 (TRPV4) is a Ca2+ -permeable channel that can be gated by tonicity (osmolarity) and mechanical stimuli. Chondrocytes, the cells in cartilage, respond to their osmotic and mechanical environments; however, the molecular basis of this signal transduction is not fully understood. This study was undertaken to demonstrate the presence and functionality of TRPV4 in chondrocytes. Methods TRPV4 protein expression was measured by immunolabeling and Western blotting. In response to TRPV4 agonist/antagonists, osmotic stress, and interleukin-1 (IL-1), changes in Ca2+ signaling, cell volume, and prostaglandin E2 (PGE2) production were measured in porcine chondrocytes using fluorescence microscopy, light microscopy, or immunoassay, respectively. Results TRPV4 was expressed abundantly at the RNA and protein levels. Exposure to 4,-phorbol 12,13-didecanoate (4,PDD), a TRPV4 activator, caused Ca2+ signaling in chondrocytes, which was blocked by the selective TRPV4 antagonist, GSK205. Blocking TRPV4 diminished the chondrocytes' response to hypo-osmotic stress, reducing the fraction of Ca2+ responsive cells, the regulatory volume decrease, and PGE2 production. Ca2+ signaling was inhibited by removal of extracellular Ca2+ or depletion of intracellular stores. Specific activation of TRPV4 restored the defective regulatory volume decrease caused by IL-1. Chemical disruption of the primary cilium eliminated Ca2+ signaling in response to either 4,PDD or hypo-osmotic stress. Conclusion Our findings indicate that TRPV4 is present in articular chondrocytes, and chondrocyte response to hypo-osmotic stress is mediated by this channel, which involves both an extracellular Ca2+ and intracellular Ca2+ release. TRPV4 may also be involved in modulating the production or influence of proinflammatory molecules in response to osmotic stress. [source] Identification of interleukin-7 as a candidate disease mediator in spondylarthritis,ARTHRITIS & RHEUMATISM, Issue 11 2008Markus Rihl Objective Understanding of the molecular pathophysiology of spondylarthritis (SpA) remains largely elusive. This is related both to the complexity of the disease (axial versus peripheral disease, inflammation versus tissue remodeling) and to the difficulty in obtaining samples from primary disease sites. This study was undertaken to explore a gene expression approach for identifying novel candidate mediators of SpA. Methods Sacroiliac joint fluid aspirates from 3 SpA patients with active sacroiliitis were studied by microarray analysis. The expression of selected candidate molecules in peripheral synovitis was confirmed by reverse transcriptase,polymerase chain reaction and enzyme-linked immunosorbent assay. Results Microarray analysis identified 4 sacroiliitis gene clusters, containing a total of 47 messenger RNA (mRNA) transcripts. Two clusters contained genes expressed in all sacroiliitis samples, corresponding to both known and unsuspected candidate mediators of SpA pathology. These included proinflammatory molecules as well as molecules involved in tissue remodeling, such as transforming growth factor ,2. Of the novel candidate genes selected for confirmation, interleukin-7 (IL-7) mRNA expression was higher in SpA peripheral synovial fluid and synovial tissue samples than in osteoarthritis samples, and similar to expression in rheumatoid arthritis (RA) samples. At the protein level, synovial fluid IL-7 levels were even higher in SpA than in RA, despite lower levels of tumor necrosis factor , and IL-1,. Conclusion In the present study, both known and unsuspected candidate mediators of SpA pathogenesis were identified, including IL-7. The specific overexpression of IL-7 at sites of peripheral synovitis in SpA suggests that further functional investigations of the role of this cytokine in SpA pathogenesis are warranted. [source] Cellular immune responses in autoimmune thyroid diseaseCLINICAL ENDOCRINOLOGY, Issue 4 2004A. P. Weetman Summary Recent research in autoimmune thyroid disease (AITD) has largely focused on delineation of the autoantigens and their epitopes, but there is now renewed interest in the immunoregulatory properties of T cells, an understanding of which may explain the emergence of AITD in experimental settings. T cell recognition of autoantigens has shown considerable intra- and interindividual heterogeneity, and a mixed pattern of cytokine production indicates that both the Th1 and Th2 limbs of the helper T cell response are involved in all types of AITD. It is now clear that secretion of chemokines and cytokines within the thyroid accounts for the accumulation and expansion of the intrathyroidal lymphocyte pool, and that the thyroid cells themselves contribute to this secretion. The thyroid cells also produce a number of proinflammatory molecules which will tend to exacerbate the autoimmune process. Thyroid cell destruction in autoimmune hypothyroidism is dependent on T cell-mediated cytotoxicity with the likely additional effect of death receptor-mediated apoptosis. [source] | |||||||||||||