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At least 1,423 records · Page 79Linked to original sources
PubMed2004

The anti-inflammatory carbazole, LCY-2-CHO, inhibits lipopolysaccharide-induced inflammatory mediator expression through inhibition of the p38 mitogen-activated protein kinase signaling pathway in macrophages.

1. The present study was undertaken to investigate the anti-inflammatory effects of a synthetic compound, LCY-2-CHO, on the expression of inducible nitric oxide synthase (iNOS), COX-2, and TNF-alpha in murine RAW264.7 macrophages. 2. Within 1-30 microm, LCY-2-CHO concentration-dependently inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO), prostaglandin E(2) (PGE(2)), and tumor necrosis factor-alpha (TNF-alpha) formation, with IC(50) values of 2.3, 1, and 0.8 microm, respectively. Accompanying inhibition of LPS-induced iNOS, cyclooxygenase-2 (COX-2), and pro-TNF-alpha proteins was observed. 3. Reverse transcription-polymerase chain reaction (RT-PCR) and promoter analyses indicated that iNOS expression was inhibited at the transcriptional level (IC(50)=2.3 microm), that inhibition of COX-2 expression only partially depended on gene transcription (IC(50)=7.6 microm), and that TNF-alpha transcription was unaffected. 4. Transcriptional assays revealed that activation of AP-1, but not NF-kappaB, was concomitantly blocked by LCY-2-CHO. Our results showed that LCY-2-CHO was capable of interfering with post-transcriptional regulation, altering the stability of COX-2 and TNF-alpha mRNAs. 5. Since the 3'-untranslated region (3' UTR) of both COX-2 and TNF-alpha mRNA contains a p38 mitogen-activated protein kinase (MAPK)-regulated element involved in mRNA stability, we assessed the effect of LCY-2-CHO on p38 MAPK. Our data clearly indicated an inhibition (IC(50)=1.7 microm) of LPS-mediated p38 MAPK activity, but not of extracellular signal-regulated kinase (ERK) or c-Jun N-terminal kinase (JNK) activity. However, kinase assays ruled out a direct inhibition of p38 MAPK action. The selective p38 MAPK inhibitor, SB203580, inhibited the promoter activities of iNOS and COX-2 rather than that of TNF-alpha. 6. In conclusion, LCY-2-CHO downregulates inflammatory iNOS, COX-2, and TNF-alpha gene expression in macrophages through interfering with p38 MAPK and AP-1 activation.

Animals↗
PubMed2006

Soluble triggering receptor expressed on myeloid cells and the diagnosis of pneumonia and severe sepsis.

The triggering receptor expressed on myeloid cells (TREM)-1 is a recently identified molecule involved in the inflammatory response. It belongs to the immunoglobulin superfamily and is expressed on the surface of neutrophils, mature monocytes, and macrophages. The engagement of TREM-1 synergizes with the Toll-like receptors signaling pathway in amplifying the inflammatory response mediated by several microbial components. The expression of the membrane-bound TREM-1 is strongly upregulated on monocytes during sepsis. Besides its membranous form, a soluble counterpart of TREM-1 exists that is specifically released during several infectious processes. The measurement of that soluble form in biological fluids may be useful as a diagnostic tool, especially during severe sepsis and pneumonia. Moreover, the evolutionary pattern of TREM-1 may be interesting during the follow-up of septic patients.

Biomarkers↗
PubMed2004

[Clinical study of routes of onset of inflammatory diseases in the maxillary sinuses].

Pathways of the maxillary sinus diseases is an interesting issue investigated by many authors during the past decades. The goal of this research was to study the pathways of infection spreading into the maxillary sinuses and to compare them in relation to their frequency, underlying causes and general epidemiologic characteristics of the involved population. A total number of 150 adult patients of both gender suffering different diseases of maxillary sinuses were included into the study. Pathways rising maxillary sinuses diseases were diagnosed on the basis of standard clinical procedures including CT scean and MRI of the region. We found inflammatory processes to dominate the tumorous ones (107:43 patients). Rhinogenic type of sinusitis was the most frequent disease (72 patients) while odontogenic sinusitis (35 patients) was significantly less frequent. No case of traumatic or hematogenic maxillary sinusitis was found. Rhinogenic maxillary sinusitis is characterised by spontaneous onset while odontogenic one is mostly of arteficial origin after surgical procedures in the oral cavity (88% of patients). In contrast to rhinogenic type, odontogenic maxillary sinusitis is far more frequent in younger patients.

Female↗
PubMed1999

Mechanism and consequences of nerve cell death in Parkinson's disease.

The etiology of Parkinson's disease remains unknown, making it difficult to develop therapeutical approaches to stop the progression of the disease. The best known treatment to date is based on the use of L-DOPA or dopaminergic agonists. These are merely substitutive therapies and have limitations because of their side effects. Thus, the development of new therapeutical strategies will require a far better knowledge of the mechanism and the consequences of nerve cell death in Parkinson's disease. Parkinson's disease is characterized by a selective vulnerability of sub-populations of dopaminergic neurons in the mesencephalon. The fact that the neurons which degenerate in Parkinson's disease are already sensitive to oxidative stress in control subjects and the reported increased production of oxygen free radicals in Parkinson's disease suggest that oxidative stress may be involved in the mechanism of nerve cell death. Furthermore, oxygen free radicals are also involved in an oxygen-dependent pro-apoptotic pathway stimulated by the inflammatory reaction observed in Parkinson's disease. These data suggest that anti-oxidant or anti-inflammatory treatments may slow down the progression of the disease. On the other hand, new substitutive therapies may be developed by trying to restore the activity of the neurons located downstream from the nigrostriatal pathway. Indeed, the nigrostriatal denervation induces a hyper-activity of the output structures of the basal ganglia (internal segment of the globus pallidus and substantia nigra pars reticulata), as demonstrated in various animal models of the disease. These changes in the activity of the output structures of the basal ganglia seem to be directly induced by the hyperactivity of the glutamatergic afferent fibers from the subthalamic nucleus. The fact that L-DOPA treatment or a reduction in the activity of the subthalamic nucleus alleviate the symptoms of the disease and restore the activity of the output structures of the basal ganglia in parkinsonism suggests that these structures play a key role in the pathophysiology of the disease and could represent a potential therapeutic target.

Animals↗
PubMedDate not supplied

[The pentosephosphate pathway of carbohydrate metabolism in evaluating the pharmacologic correction of immuno-inflammatory processes in systemic connective tissue diseases].

Treatment with roxicam, rengasil and flugalin tended significantly to normalize the activity of enzymes of carbohydrate metabolism pentosophosphate pathway in the blood of patients with systemic lupus erythematosus and rheumatoid arthritis. The dynamics of the change in the activity of enzymes of pentose phosphate pathway in the blood of patients with systemic connective tissue diseases against the background of treatment with roxicam, rengasil and flugalin is the enzymological criterion in assessing efficacy of pharmacological correction of the inflammatory process in the diseases.

Adult↗
PubMed1999

Protein kinase c-dependent pathway is critical for the production of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6).

The authors hypothesized that certain PKC isoforms play an important role in the induction of pro-inflammatory cytokine (TNF-alpha, IL-1beta, IL-6) synthesis. To test this hypothesis, the cytosol-to-membrane translocation of select PKC isoforms with tested cytokine production in human monocytes cultured in vitro was correlated. It is reported that in monocytes treated with phorbol ester (PMA), translocation of PKC isoforms alpha, betaII, delta and epsilon precede cytokine synthesis. Moreover, specific inhibition of PKC translocation that occurs in the presence of Calphostin C is reflected in downstream events: lack of MAP kinases phosphorylation, loss of DNA binding ability by AP-1 transcription factor, and the reduction of pro-inflammatory cytokine synthesis. Thus, the cytosol-to-membrane translocation of PKC isoforms alpha, betaII, delta and epsilon with the subsequent activation of: (1) MAP kinases; and (2) AP-1 transcription factor, may represent critical steps in the induction of signalling cascade leading to TNF-alpha, IL-1beta, IL-6 synthesis in human monocytes.

Cells, Cultured↗
PubMed1999

Expression of C5a receptor in mouse brain: role in signal transduction and neurodegeneration.

In this study we explored the potential role of the complement derived anaphylatoxin C5a and the expression of its receptor in mouse brain. Using in situ hybridization, we found that C5a receptor messenger RNA is expressed in mouse brain. In response to intraventricular kainic acid injection, there was marked increase in the C5a receptor messenger RNA expression, particularly in hippocampal formation and cerebral cortex. C5a ligand-binding autoradiography confirmed the functional expression and elevation of the C5a receptor post-lesioning. The expression of C5a receptor messenger RNA in brain was confirmed by northern blot hybridization of total RNA from neuronal and glial cells in vitro. Based on these findings we explored the role of C5a in mechanisms of signal transduction in brain cells. Treatment of primary cultures of mouse astrocytes with human recombinant C5a resulted in the activation of mitogen-activated extracellular signal-regulated protein kinase. This response appeared to be mediated by the C5a receptor since astrocyte cultures derived from C5a receptor knockout mice were not responsive to the treatment. Understanding the regulation of C5a receptor in brain and mechanisms by which pro-inflammatory C5a modulates specific signal transduction pathways in brain cells is crucial to studies of inflammatory mechanisms in neurodegeneration.

Animals↗
PubMed2026

Association Between the Root Canal Microbiome and Apical Lesion Size: An Observational Shotgun Metagenomic Study.

AIM: The aim was to characterize the taxonomic and functional composition of the microbiome involved in primary endodontic infections and to evaluate their association with the periapical lesion size using shotgun metagenomic sequencing. METHODOLOGY: Samples from primary root canal infections diagnosed with apical periodontitis were analysed with shotgun sequencing. Samples were classified according to the lesion size as small (<&#x2009;3&#x2009;mm) or large (>&#x2009;7&#x2009;mm). The bacterial DNA copies in each group were quantified by qPCR. Taxonomic and functional annotations were made using Bracken/Kraken2 and HUMAnN3 software. Species richness, Shannon, Simpson and Pielou indices were used to measure alpha diversity. The similarity of the bacterial communities between study groups was evaluated by Principal Coordinate Analysis based on Bray-Curtis distances. The ALDEx2 package was used to infer the differences between species, and the edgeR package for KEGG pathways. For all statistical analyses, p&#x2009;<&#x2009;0.05 was considered as significant. RESULTS: A total of 49 samples were analysed, 27 with small lesions and 22 with large lesions. Species richness and Shannon indices showed differences between both groups, whereas no differences were seen according to Simpson and Pielou indices. A different community composition (PERMANOVA, p&#x2009;=&#x2009;0.0019) was observed between the two groups. Three species were significantly enriched in the large lesion samples, Filifactor alocis, Lachnospiraceae bacterium oral taxon 500 and Olsenella uli, while three others were enriched in small lesion samples, Acinetobacter baumannii, Acinetobacter pittii and Cutibacterium acnes. Functionally, benzoate, flavonoid and steroid degradation, the sphingolipid signalling pathway and proteasome function were enriched in samples with large lesions. Monoterpenoid biosynthesis, phospholipase D signalling, the sulphur relay system and staurosporine biosynthesis were enriched in small lesions. CONCLUSIONS: Teeth with large periapical lesions harbour greater bacterial loads and exhibit a more diverse microbial community than those with small lesions. Differences in species-level taxonomic composition were observed between both groups. Functionally, large lesions are enriched in pathways associated with immune evasion and pro-inflammatory activity, whereas small lesions are characterized by pathways related to apoptosis, metabolic adaptation and anti-inflammatory processes. These findings suggest that lesion severity is also shaped by the functional potential of the microbiome to modulate host inflammation.

Humans↗
PubMed2005

ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease.

Blood high-density lipoprotein (HDL) levels are inversely related to risk for cardiovascular disease, implying that factors associated with HDL metabolism are atheroprotective. One of these factors is ATP-binding cassette transporter A1 (ABCA1), a cell membrane protein that mediates the transport of cholesterol, phospholipids, and other metabolites from cells to lipid-depleted HDL apolipoproteins. ABCA1 transcription is highly induced by sterols, a major substrate for cellular export, and its expression and activity are regulated posttranscriptionally by diverse processes. Liver ABCA1 initiates formation of HDL particles, and macrophage ABCA1 protects arteries from developing atherosclerotic lesions. ABCA1 mutations can cause a severe HDL deficiency syndrome characterized by cholesterol deposition in tissue macrophages and prevalent atherosclerosis. Genetic manipulations of ABCA1 expression in mice also affect plasma HDL levels and atherogenesis. Metabolites elevated in individuals with the metabolic syndrome and diabetes destabilize ABCA1 protein and decrease cholesterol export from macrophages. Moreover, oxidative modifications of HDL found in patients with cardiovascular disease reduce the ability of apolipoproteins to remove cellular cholesterol by the ABCA1 pathway. These observations raise the possibility that an impaired ABCA1 pathway contributes to the enhanced atherogenesis associated with common inflammatory and metabolic disorders. The ABCA1 pathway has therefore become an important new therapeutic target for treating cardiovascular disease.

ATP Binding Cassette Transporter 1↗
PubMed2006

Nonredundant roles of TIRAP and MyD88 in airway response to endotoxin, independent of TRIF, IL-1 and IL-18 pathways.

Inhaled endotoxins induce an acute inflammatory response in the airways mediated through Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). However, the relative roles of the TLR4 adaptor proteins TIRAP and TRIF and of the MyD88-dependent IL-1 and IL-18 receptor pathways in this response are unclear. Here, we demonstrate that endotoxin-induced acute bronchoconstriction, vascular damage resulting in protein leak, Th1 cytokine and chemokine secretion and neutrophil recruitment in the airways are abrogated in mice deficient for either TIRAP or MyD88, but not in TRIF deficient mice. The contribution of other TLR-independent, MyD88-dependent signaling pathways was investigated in IL-1R1, IL-18R and caspase-1 (ICE)-deficient mice, which displayed normal airway responses to endotoxin. In conclusion, the TLR4-mediated, bronchoconstriction and acute inflammatory lung pathology to inhaled endotoxin critically depend on the expression of both adaptor proteins, TIRAP and MyD88, suggesting cooperative roles, while TRIF, IL-1R1, IL-18R signaling pathways are dispensable.

Adaptor Proteins, Vesicular Transport↗
PubMed2005

The hedgehog signalling pathway in the gastrointestinal tract: implications for development, homeostasis, and disease.

The hedgehog signalling pathway is critical to normal mammalian gastrointestinal development. Through epithelial-mesenchymal interactions, hedgehog signalling ensures appropriate axial patterning of the embryonic gut. Congenital abnormalities, including malrotations, anorectal malformations, and tracheoesophageal fistula are associated with germ-line mutations/deletion of genes encoding hedgehog signalling components in man and present in genetically engineered animal models. In adults, there is evidence that the pathway plays a role in maintaining stem cell populations in the stomach and directing epithelial cell differentiation in the intestine. Recent data implicate hedgehog signalling in the formation and maintenance of a number of malignancies, including those of the upper gastrointestinal (GI) tract and pancreas, in which abrogation of the pathway offers a novel therapeutic approach in animal models. Most recently, evidence in vitro indicates that there is a recapitulation of embryonic hedgehog signalling in acute epithelial injury and chronic inflammation, a finding with key implications for inflammatory disorders of the intestine, such as inflammatory bowel diseases. This pathway may provide an important link between chronic inflammation and cancer. We summarize the available evidence demonstrating that this developmental pathway has continuing roles in adult homeostasis and is dysregulated in malignancy and inflammation of the gastrointestinal tract.

Animals↗
PubMed2005

Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK.

Tumor-associated macrophages may influence tumor progression, angiogenesis and invasion. To investigate mechanisms by which macrophages interact with tumor cells, we developed an in vitro coculture model. Previously we reported that coculture enhanced invasiveness of the tumor cells in a TNF-alpha- and matrix metalloprotease-dependent manner. In this report, we studied intracellular signaling pathways and induction of inflammatory genes in malignant cells under the influence of macrophage coculture. We report that coculture of macrophages with ovarian or breast cancer cell lines led to TNF-alpha-dependent activation of JNK and NF-kappaB pathways in tumor cells, but not in benign immortalized epithelial cells. Tumor cells with increased JNK and NF-kappaB activity exhibited enhanced invasiveness. Inhibition of the NF-kappaB pathway by TNF-alpha neutralizing Abs, an NF-kappaB inhibitor, RNAi to RelA, or overexpression of IkappaB inhibited tumor cell invasiveness. Blockade of JNK also significantly reduced invasiveness, but blockade of p38 MAPK or p42 MAPK had no effect. Cocultured tumor cells were screened for the expression of 22 genes associated with inflammation and invasion that also contained an AP-1 and NF-kappaB binding site. EMMPRIN and MIF were up-regulated in cocultured tumor cells in a JNK- and NF-kappaB-dependent manner. Knocking down either MIF or EMMPRIN by RNAi in the tumor cells significantly reduced tumor cell invasiveness and matrix metalloprotease activity in the coculture supernatant. We conclude that TNF-alpha, via NF-kappaB, and JNK induces MIF and EMMPRIN in macrophage to tumor cell cocultures and this leads to increased invasive capacity of the tumor cells.

Antigens, CD↗
PubMed2003

Science review: Genetic variability in the systemic inflammatory response.

The present review discusses recent studies that have identified genetic differences in inflammatory proteins associated with different phenotypic presentations of systemic inflammation. Basic genetic terminology is defined. Implications of genetic influences on the inflammatory response are discussed. The published associations of specific polymorphisms in antigen recognition pathways, proinflammatory cytokines, anti-inflammatory cytokines, and effector molecules are reviewed. The strongest and most consistent associations thus far have been with the tumor necrosis factor, lymphotoxin-alpha, and IL-1 receptor antagonist polymorphisms. However, large, phenotypically detailed studies are required to address all of the other potential polymorphisms in inflammatory molecule genes and their interactions.

Cytokines↗
PubMed1990

Temporal expression of different pathways of 1-arginine metabolism in healing wounds.

Arginine can be metabolized by inflammatory cells through at least two pathways. One is an oxidative l-arginine deiminase (OAD) that results in the formation of citrulline and reactive nitrogen intermediates. The other is arginase, which determines the production of ornithine and urea. The temporal expression of these pathways in an experimental wound model (s.c. implanted polyvinyl alcohol sponges in the rat) was investigated by examining the concentrations of amino acids and of nitrite in fluids obtained from the sponges 6 h to 15 day after implantation. These analyses revealed two distinct periods during which the arginine concentration in the fluids was markedly below plasma levels. During the early period (less than 3 days after sponge implantation) wound fluid contained more citrulline and nitrite than at any other time, suggesting OAD activity. In contrast, ornithine accumulated in the fluids during the late decrease in arginine concentration that extended beyond day 3, during which time the wound fluid also contained a high arginase activity. This time-dependent expression of different pathways of arginine metabolism in wounds was confirmed in sponge cultures containing [guanido-14C]-l-arginine. Cells contained in sponges harvested less than 48 h after implantation metabolized labeled arginine mainly to labeled citrulline, whereas labeled urea was produced during culture of sponges harvested after this time. The low arginine content of wound fluid did not appear to be rate limiting for the expression of OAD in late sponges because no OAD activity was evidenced when 4 mM arginine was added to the cultures. These results indicate that the OAD pathway is expressed in this model predominantly during the early, polymorphonuclear leukocyte-predominant, phase of repair. At this time, the reactive nitrogen intermediates resulting from the metabolism of arginine may mediate some of the events characteristic of early inflammation, including microbiostasis, vasodilation, and inhibition/reversal of platelet aggregation. In turn, the late suppression of this pathway and the catabolism of arginine through arginase may promote macrophage function within wounds.

Animals↗
PubMedDate not supplied

[Inflammatory mechanisms, arteriosclerosis and ischemic stroke: clinical data and perspectives].

OBJECTIVE: The atherosclerosis is the most common cause of death and disability in developed countries by causing ischemic cardiopathic and stroke. The ischemic atherotrombotic stroke is the most frequent form of the last one. In this sense we review herein the mechanisms underlying the artherosclerotic process. DEVELOPMENT: It is understood as an inflammatory disease, by taking into account the widely accepted hypothesis by Ross: it was firstly stated in structural terms, as macrophages and T/B linfocities were present in the arterial wall from the first stages of the disease (fatty streak) to the last and complicated ones. The starting point is a functional endothelial damage, secondary to mechanical or vascular risk factors and called response to injury hypothesis . The next step is an inflammatory cascade that involves humoral (citokines, growth factors) and cellular (increased quimiotaxis, adherece and infiltration of inflamatory cells) mechanisms. They interact among them, outbalanced and in a progresssive way that leads to the final fibroproliferative response. Every stage has his own inflammatory components and interactive pathways. The following elements are outstanding in this process: 1) Adhesion molecules, including E selectin, ICAM 1 and VCAM 1, that are increased locally in the plaques and as circulating elements; plaquetary receptors of the type IIb/IIIa are integrins wich belong to the same family; 2) Citokines with either proinflammatory activity like IL 1, the TNF a and linfocitary ligands like the CD 40, or with antiinflammatory activity like the gamma interpheron; 3) Growth factors, with plaquetary (PDGF) and fibroblastic (FGF) variants as the cornerstone; 4) Markers of systemic inflammation, overall plasma C reactive protein and fibrinogen, that predict the risk of stroke and cardiovascular death; IL 6, complement, thrombin and heat shock proteins (HSP) would act in a similar but less conclusive way. CONCLUSIONS: The evidences of the pivotal role of the inflammation in the stroke allow to develop therapeutical strategies to prevent the disease: fostering natural antiinflamatory mechanisms, or inhibiting inflammatory elements by selective (monoclonal antibodies) or non selective (IIb/IIIa receptors, antiinflammatory drugs) pathways are distinctily glimpsed, ongoing or fully developed.

Arteriosclerosis↗
PubMed2006

Direct modulation of rheumatoid inflammatory mediator expression in retinoblastoma protein-dependent and -independent pathways by cyclin-dependent kinase 4/6.

OBJECTIVE: It is known that the cyclin-dependent kinase inhibitor (CDKI) gene p21(Cip1) suppresses rheumatoid inflammation by down-modulating type I interleukin-1 receptor (IL-1RI) expression and inhibiting JNK activity. The purpose of this study was to determine whether CDK activity directly modulates the production of inflammatory molecules in patients with rheumatoid arthritis (RA). METHODS: Genes for the CDKIs p16(INK4a) and p18(INK4c), a constitutively active form of retinoblastoma (RB) gene product, cyclin D1, and CDK-4, were transferred into RA synovial fibroblasts (RASFs). RASFs were also treated with a synthetic CDK-4/6 inhibitor (CDK4I). Levels of matrix metalloproteinase 3 (MMP-3), monocyte chemoattractant protein 1 (MCP-1), and IL-1RI expression were determined by Northern blotting, real-time polymerase chain reaction analysis, and enzyme-linked immunosorbent assay. CDKIs were immunoprecipitated to reveal their association with JNK. RESULTS: Transfer of the p16(INK4a) and p18(INK4c) genes and CDK4I suppressed the production of MMP-3 and MCP-1. Unlike p21(Cip1), neither CDKI gene inhibited IL-1RI or JNK. The expression of MMP-3 was up-regulated when CDK-4 activity was augmented. This regulation functioned at the messenger RNA (mRNA) level in MMP-3, but not in MCP-1. Transfer of active RB suppressed the production of MMP-3 and MCP-1 without changing their mRNA levels. CONCLUSION: CDK-4/6 modulated the production of MMP-3 and MCP-1. MMP-3 production was regulated primarily at the mRNA level in an RB-independent manner, whereas MCP-1 production was controlled posttranscriptionally by RB. These results show that cell cycle proteins are associated with control of mediators of inflammation through multiple pathways.

Arthritis, Rheumatoid↗
PubMed2004

Conventional protein kinase C and atypical protein kinase Czeta differentially regulate macrophage production of tumour necrosis factor-alpha and interleukin-10.

In chronic inflammatory diseases such as rheumatoid arthritis, joint macrophages/monocytes are the major source of pro- and anti-inflammatory cytokines. Little is understood regarding the signalling pathways which determine the production of the pro-inflammatory cytokine, tumour necrosis factor-alpha (TNF-alpha) and the anti-inflammatory cytokine, interleukin-10 (IL-10). Two pathways integral to macrophage function are the protein kinase C (PKC)- and the cAMP-dependent pathways. In this report, we have investigated the involvement of PKC and cAMP in the production of TNF-alpha and IL-10 by peripheral blood monocyte-derived macrophages. The utilization of the PKC inhibitors Go6983, Go6976 and RO-32-0432 demonstrated a role for conventional PKCs (alpha and beta) in the production of TNF-alpha in response to stimulation by lipopolysaccharide and phorbol 12-myristate 13-acetate (PMA)/ionomycin. PKC stimulation resulted in the downstream activation of the p42/44 mitogen-activated protein kinase (MAPK) pathway which differentially regulates TNF-alpha and IL-10. The addition of cAMP however, suppressed activation of this MAPK and TNF-alpha production. Cyclic-AMP augmented IL-10 production and cAMP response element binding protein activation upon stimulation by PMA/ionomycin. In addition, cAMP activated PKCzeta; inhibition of which, by a dominant negative adenovirus construct, selectively suppressed IL-10 production. These observations suggest that pro-inflammatory and anti-inflammatory cytokines are differentially regulated by PKC isoforms; TNF-alpha being dependent on conventional PKCs (alpha and beta) whereas IL-10 is regulated by the cAMP-regulated atypical PKCzeta.

Cells, Cultured↗