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Toll-like receptor 2 (TLR2) plays a crucial role in detecting microbial pathogen-associated molecular patterns, offering potential applications as an adjuvant for vaccines and antitumor therapies. Here, we present the gram-scale synthesis of CaLGL-1 and its derivatives, natural products known for activating mouse TLR2 (EC50 = 3.2 µM). This synthesis involves a streamlined six-step reaction sequence utilizing oxidant-promoted acetalization, effectively preserving the acid-sensitive glycosidic bond for maintaining the compounds' functional integrity. Our structure-activity relationship studies identified R-7d as a potent human TLR2 activator. It demonstrated subnanomolar activity (EC50 = 116 pM) in human THP-1 cells, comparable to that of diprovocim (EC50 = 110 pM). Experiments revealed that R-7d enhances NF-kB promoter activation through TLR2/TLR1 heterodimers rather than TLR2/TLR6. The discovery of R-7d as a robust human TLR2 agonist opens up new possibilities for combination therapies.
Assuntos
Receptor 2 Toll-Like , Humanos , Receptor 2 Toll-Like/agonistas , Receptor 2 Toll-Like/metabolismo , Relação Estrutura-Atividade , Células THP-1 , NF-kappa B/metabolismo , Receptor 1 Toll-Like/agonistas , Receptor 1 Toll-Like/metabolismoRESUMO
Imidazolium-based poly(ionic liquid)s were synthesized and used as sensing film for the adsorption of volatile organic compounds. Based on a quartz crystal microbalance system, the sensing properties of the imidazolium-based poly(ionic liquid)s on volatile organic compounds was assessed according to the position of imidazolium cation in the polymer chain (the main-chain or side-chain type) and the varied counterions. The results indicated that the imidazolium-based poly(ionic liquid)s films have much higher adsorption capability on volatile organic acids than other volatile organic compounds, which is due to the strong affinity between imidazolium group and the carboxyl group. The position of imidazolium cation in the polymer chain and counterions of the imidazolium-based poly(ionic liquid)s was found to be able to influence the selectivity and sensitivity of volatile organic acids. The main-chain imidazolium-based poly(ionic liquid)s were shown strengthen the adsorption of propionic acid vapor, while the counter ion of dicyanamide showed the highest selectivity on volatile organic acids. Based on the quartz crystal microbalance sensing system, the imidazoliumbased poly(ionic liquid)s film was shown capable of detecting volatile organic acids with a theoretical detection limit of about 3.1 ppb and a quick recovery time less than 40 seconds. The sensing performance is also stable for repeated usage and after long-time storage.
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Phosphodiesterase 4 (PDE4) has four subtypes: PDE4A, PDE4B, PDE4C and PDE4D. The expression of PDE4 subtypes in microglial cells and the specific contribution of each subtype to inflammation remain unclear. In this study, the expression of PDE4 subtypes in primary microglial cells was assayed. Primary microglial cells were then transfected with specific small interfering RNA (siRNA) against each PDE4 subtype. PDE4 subtype A-D knockdown was confirmed by quantitative polymerase chain reaction. Secreted cytokines in the supernatant and intracellular cyclic adenosine monophosphate (cAMP) levels of transfected cells were measured. The effect of PDE4B siRNA on the activation of extracellular regulated protein kinase (ERK) induced by lipopolysaccharide (LPS) in microglia was further tested by western blotting. Results showed that the primary microglial cells expressed all four types of PDE4s at the protein level. Transfection with the four siRNAs inhibited PDE4 subtype A-D mRNA expression, respectively. In primary microglial cells, treatment with PDE4B siRNA significantly inhibited the expression of tumor necrosis factor-α and interleukin (IL)-1ß, and enhanced the expression of cAMP, while siRNAs to other subtypes had no significant effects. However, none of the four siRNAs had any significant effect on the expression of IL-10. Furthermore, in the PDE4B group, the level of phosphorylated ERK was reduced. Among the four PDE4 subtypes, PDE4B plays an important role in regulating inflammatory responses in microglia, potentially through initially regulating the intracellular cAMP concentration.
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The molecular mechanisms underlying neuropathic pain have yet to be elucidated. The present study aimed to examine the modulation of neuroimmune activation in the spinal cord by the synthetic peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, pioglitazone (Pio), in a rat model of neuropathic pain induced by chronic constriction injury (CCI). Rats were randomly assigned into four groups: Sham surgery with vehicle, chronic constriction injury with vehicle or Pio (10 mg/kg), and chronic constriction injury with Pio and a PPAR-γ antagonist GW9662 (2 mg/kg). Pio or vehicle was administered 1 h prior to the surgery and continued daily until day 7 post-surgery. Paw pressure threshold was measured prior to surgery and on days 0, 1, 3 and 7 post-surgery. Microglia activation markers macrophage antigen complex-1, the mRNA expression levels of tumor necrosis factor α and interleukin-1ß, and the mRNA expression levels of toll like receptor (TLR-4) in the lumbar spinal cord were determined. Administration of Pio resulted in the prominent attenuation of mechanical hyperalgesia. In addition, Pio was able to significantly inhibit neuroimmune activation characterized by glial activation, the production of cytokines and expression levels of TLR-4. Concurrent administration of a PPAR-γ antagonist, GW9662, reversed the effects of Pio. The antihyperalgesic effect of administration of Pio in rats receiving CCI may, in part, be attributed to the inhibition of neuroimmune activation associated with the sustaining of neuropathic pain.
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Neuroimmune activation contributes to the generation and maintenance of neuropathic pain after peripheral nerve injury. Peroxisome proliferator activated receptor gamma (PPAR-γ) agonists have potential neuroprotection. The current study aimed to determine the effects of a PPAR-γ agonist pioglitazone on mechanical hyperalgesia and neuroimmune activation in a rat model of neuropathic pain induced by L5 spinal nerve transection (SNT). Thirty-two rats were equally randomized into 4 groups: sham operation with vehicle; L5 SNT with vehicle or pioglitazone; or L5 SNT with pioglitazone and a PPAR-γ antagonist GW9662. Pioglitazone or vehicle was administered 1h before operation and continued daily to day 14 after operation. The paw pressure threshold (PPT) was measured before operation and on days 3, 7, 14 after operation. Glial fibrillary acidic protein (GFAP) expression, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 levels, and nuclear factor-kappa B (NF-κB) activity in the lumbar spinal cord were determined on day 14 after operation. The results displayed pioglitazone improved the mechanical hyperalgesia, and attenuated the astrocyte and NF-κB activation and the inflammatory cytokine upregulation in nerve-injured rats, which might be reversed by GW9662. In conclusion, pioglitazone ameliorates the mechanical hyperalgesia induced by L5 SNT via inhibiting the spinal neuroimmune activation in rats, suggesting spinal PPAR-γ signaling pathway may be involved in the pathogenesis of mechanical hyperalgesia.
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Proteína Glial Fibrilar Ácida/metabolismo , Neuralgia/tratamento farmacológico , Neuroimunomodulação , Fármacos Neuroprotetores/farmacologia , PPAR gama/agonistas , Medula Espinal/efeitos dos fármacos , Nervos Espinhais/lesões , Tiazolidinedionas/farmacologia , Animais , Citocinas/metabolismo , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Masculino , NF-kappa B/metabolismo , Neuralgia/imunologia , Neuralgia/fisiopatologia , Fármacos Neuroprotetores/uso terapêutico , Limiar da Dor , Pioglitazona , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Medula Espinal/imunologia , Medula Espinal/metabolismo , Tiazolidinedionas/uso terapêutico , TatoRESUMO
Recent studies indicate the central neuroimmune and neuroinflammation activation play a critical role in the pathological states of pain. Pioglitazone, a potent synthetic agonists of PPARgamma, has shown to control neuroinflammation in many nervous system-related disorders. The present study was designed to explore the effects of pioglitazone in treating neuropathic pain and its possible neuroimmune mechanisms in the neuropathic pain using lumbar 5 (L5) spinal nerve transection rat model. L5 spinal nerve transection was done to produce hyperalgesia in rats. Pioglitazone (2.5, 5, and 10 mg/kg) was orally administered daily for 14 days, beginning from 1 hour before nerve transection. Mechanical hyperalgesia was measured using Von-Frey filament tests before and after the surgery. Rats were then sacrificed on day 14 postsurgery. The mRNA of inflammatory cytokines such as tumor necrosis factor (TNF-alpha), interleukin (IL-1beta) and nuclear factor kappa B (NF-kappaB) activity in brain were detected using reverse transcription-polymerase chain reaction and electrophoretic mobility shift assay. We found that pioglitazone (5 and 10 mg/kg) can markedly attenuate mechanical hyperalgesia produced by nerve transection, most significantly on the 14th day. The elevated TNF-alpha, IL-1beta, and NF-kappaB in brain were accordingly reduced. Our data could conclude that pioglitazone has ameliorative potential in attenuating the painful state associated with L5 nerve transection, which may further be attributed to inhibiting cerebral proinflammatory cytokines production and NF-kappaB activation in central nervous system.
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Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Tiazolidinedionas/administração & dosagem , Animais , Encéfalo/metabolismo , Citocinas/biossíntese , Citocinas/metabolismo , Modelos Animais de Doenças , Hiperalgesia/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , NF-kappa B/metabolismo , Neuralgia/metabolismo , Neuroimunomodulação/efeitos dos fármacos , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Pioglitazona , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Nervos Espinhais/cirurgia , Tiazolidinedionas/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
INTRODUCTION: Brains are often subject to injurious effect following remote burn injury and increased productions of inflammatory cytokines are involved. It is also known that pentoxifylline (PTX) exerts multiple beneficial effects on the inflammatory cascade. Therefore, we investigated whether a single dose of PTX given immediately following severe remote burn would protect the brain from the injurious effects. METHODS: Rats were divided randomly into the sham burn group, burn placebo-treated group and burn PTX-treated group. Single dose of PTX was injected 15 min following initial burn injury. We measured the levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-10 in the brain tissue at 0.5, 1, 2, 4, 8 and 16 h after burn. Other measures included the level of nuclear factor-kappaB (NF-κB) activation, glial activation and apoptosis of cortical cells. RESULTS: PTX substantially suppressed the burn-induced surge in the levels of TNF-α, IL-1ß, and IL-6 in the rat-brain tissues. PTX reduced the level of burn-induced apoptosis. PTX also significantly reduced the activation of nuclear transcription factor NF-κB and reduced the activation of glial cells in the brain tissue. CONCLUSION: An early, single dose of PTX dramatically reduced brain inflammation and apoptosis for up to 16 h post-injury.
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Anti-Inflamatórios/uso terapêutico , Encéfalo/efeitos dos fármacos , Queimaduras/complicações , Fármacos Neuroprotetores/uso terapêutico , Pentoxifilina/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Animais , Apoptose/fisiologia , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Queimaduras/tratamento farmacológico , Queimaduras/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Imuno-Histoquímica , Inflamação/metabolismo , Inflamação/patologia , Masculino , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/análise , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismoRESUMO
PURPOSE: To compare the effects of retroperitoneal laparoscopic surgery (RPL) and transperitoneal laparoscopic surgery (TPL) on the hemodynamic and ventilatory functions in old patients. METHODS: Thirty-two senior patients underwent either RPL or TPL. Swan-Ganz and radial artery catheters were placed to monitor hemodynamic functions. Artery blood samples were obtained to analyze ventilatory functions. RESULTS: For hemodynamic changes in both TPL and RPL, central venous pressure, mean pulmonary arterial pressure and pulmonary capillary wedge pressure significantly increased 10 min after CO(2) insufflation and decreased to preanesthesia levels roughly 30 min after insufflation relief. For ventilatory functions, in both TPL and RPL, peak airway pressure, partial pressure of arterial carbon dioxide (PaCO(2)), end-tidal carbon dioxide tension (PetCO(2)), carbon dioxide output (VCO(2)), and the difference between PaCO(2) and PetCO(2) (Pa-PetCO(2)) all increased significantly 10 min after CO(2) insufflation and returned to the preanesthesia level 20 min after CO(2) desufflation. However, increments of PaCO(2), VCO(2) and Pa-PetCO(2) were significantly higher in RPL than in TPL, and did not return to the preanesthesia level until 30 min after CO(2) desufflation. CONCLUSION: For senior patients, TPL and RPL have similar effects on hemodynamic functions. However, RPL tends to cause much more change in the respiratory measurements.
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Hemodinâmica , Laparoscopia/métodos , Respiração , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Peritônio , Espaço RetroperitonealRESUMO
PURPOSE: The effect of recombinant human erythropoietin (rhEPO) on neuropathic pain remains unclear. This study aimed to determine the effects of preemptive administration of rhEPO on the behavioural changes and neuroinflammatory responses in a rat model of neuropathic pain. METHODS: Fifty rats were randomly allocated into five groups, sham-operation treated with saline and L5 spinal nerve transection treated with different doses of rhEPO (0 [saline], 1000, 3000, or 5000 U x kg(-1), respectively). The rats were intraperitoneally treated from 1 day before surgery to post-surgery day 7. The mechanical (paw pressure thresholds, PPT) and thermal thresholds (paw withdrawal latencies, PWL) were measured on post-surgery days 1, 3, and 7. The contralateral brain was obtained on post-surgery day 7 to determine the expressions of tumour necrosis factor (TNF-alpha), interleukin (IL)-1beta, IL-6, L-10, and nuclear factor-kappa B (NF-kappaB) activity. RESULTS: There were significant decreases in PPT and PWL after L5 spinal nerve transection (P < 0.001). Compared with the saline group, the rhEPO 3000 and 5000 U x kg(-1) groups resulted in significant increases in PPT and PWL (P < 0.001) and reduced the cerebral expressions of TNF-alpha, IL-1beta, IL-6, and NF-kappaB activity associated with the increase in IL-10 (rhEPO3000 group, P < 0.05, and rhEPO5000 group, P < 0.001, respectively). Administration of rhEPO 1000 U x kg(-1) had no significant effects on these variables. CONCLUSIONS: Preemptive rhEPO dose-dependently attenuated the mechanical and thermal hyperalgesia in L5 spinal nerve transection rats, which correlated with the decreased cerebral expressions of TNF-alpha, IL-1beta, and IL-6 via downregulating NF-kappaB activity and the increased expression of IL-10.
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Citocinas/efeitos dos fármacos , Eritropoetina/farmacologia , NF-kappa B/efeitos dos fármacos , Neuralgia/tratamento farmacológico , Medição da Dor/métodos , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eritropoetina/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , NF-kappa B/metabolismo , Neuralgia/metabolismo , Limiar da Dor/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes , Fator de Necrose Tumoral alfa/efeitos dos fármacosRESUMO
Neuropathic pain is a complex syndrome resulting from damage to the peripheral nervous system. Central neuroimmune activation contributes to the generation and maintenance of chronic pain after nerve injury. The current study determined the effects of recombinant human erythropoietin (rhEPO) on behavioral hyperalgesia and neuroimmune activation in a rat model of neuropathic pain induced by L5 spinal nerve transection. Animals were randomly assigned into 3 groups: sham-operation with saline; L5 spinal nerve transection with rhEPO (5000 units/kg); or L5 transection with saline. The rhEPO or saline was given ip on the day before surgery and continued daily to day 7 post-transection. The paw pressure threshold and paw withdrawal latencies were measured before surgery and on days 1, 3, and 7 post-operation. Glial activation markers such as macrophage antigen complex-1 (Mac-1, OX-42) and glial fibrillary acidic protein (GFAP), production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-10, as well as nuclear factor-kappa B (NF-kappaB) activation were determined in the lumbar spinal cord. Administration of rhEPO resulted in attenuation of mechanical and thermal hyperalgesia. Furthermore, rhEPO markedly inhibited neuroimmune activation characterized by glial activation, production of proinflammatory cytokines like TNF-alpha, IL-1beta, and NF-kappaB activation, but rhEPO enhanced the level of IL-10. These results support the significance of neuroinflammation and neuroimmune activation in the initiation and persistence of behavioral pain responses. The data indicate that rhEPO attenuates behavioral hyperalgesia and neuroimmune activation in neuropathic pain induced by L5 nerve transection.
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Eritropoetina/farmacologia , Eritropoetina/uso terapêutico , Neuralgia/tratamento farmacológico , Neuroimunomodulação/efeitos dos fármacos , Nervos Espinhais/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Citocinas/biossíntese , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Hiperalgesia/tratamento farmacológico , Mediadores da Inflamação/metabolismo , Masculino , NF-kappa B/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Medição da Dor , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Nervos Espinhais/efeitos dos fármacos , Nervos Espinhais/cirurgia , TemperaturaRESUMO
AIM: To investigate whether pentoxifylline (PTX) could influence the increased cytokine gene expression in the retina flowing transient ischemia, and if so, whether it acts through the modulation of nuclear factor kappa B (NF-kappaB) activation. METHODS: Sprague-Dawley rats were randomly divided into three equal groups: control group, saline-treated group, and PTX-treated group. Increased intraocular pressure was applied for 90 min to induce retinal ischemia, and reperfusion was established by lowering the bottle to eye level. The reperfusion period lasted for 48 h. In the PTX-treated group, an initial dose of 20 mg PTX was injected via tail vein at the beginning of reperfusion. Then the rat received infusion of PTX at a rate of 6 mg/kg/h throughout the entire reperfusion period. The retinal tissues were collected at the end of 1, 6, 12, 24, and 48 h of reperfusion, respectively, for biochemical analysis. Histological examination was done on the tissues collected at the end of 48 h after reperfusion. RESULTS: Histological examination revealed reduction of overall retinal thickness and thinning of the inner retinal layer in saline-treated rats after 48-hour reperfusion. However, PTX treatment significantly reduced the loss of overall retinal thickness and thinning of inner retinal layers. Dramatic increase in NF-kappaB activation, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) production and mRNA expression were observed in the saline-treated group after reperfusion, with the peak reached around 12 h. In the PTX-treated group, NF-kappaB activation, TNF-alpha and IL-1beta production and mRNA expression were significantly reduced at each corresponding time point compared to the saline-treated group. CONCLUSION: PTX decreased the up-regulated activation of NF-kappaB and the expression of proinflammatory cytokines, TNF-alpha and IL-1beta in rat retinas following ischemia/reperfusion. This may contribute to significantly reduce the loss of overall retinal thickness and thinning of inner retinal layers.
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Citocinas/biossíntese , Isquemia/tratamento farmacológico , NF-kappa B/biossíntese , Pentoxifilina/uso terapêutico , Retina/metabolismo , Doenças Retinianas/tratamento farmacológico , Regulação para Cima/efeitos dos fármacos , Animais , Citocinas/efeitos dos fármacos , Citocinas/genética , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Sequestradores de Radicais Livres/uso terapêutico , Isquemia/metabolismo , Isquemia/patologia , Masculino , NF-kappa B/efeitos dos fármacos , NF-kappa B/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Retina/ultraestrutura , Doenças Retinianas/metabolismo , Doenças Retinianas/patologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Previous studies have suggested that pentoxifylline (PTX) exerts multiple beneficial effects on the inflammatory cascade, particularly on the function of neutrophils. We investigated whether continuous infusion of PTX could reduce indirect lung injury (ILI) caused by fresh water drowning and if so, what is the possible molecular mechanism. METHODS: Twenty 4 male canis were divided randomly into control group, fresh water drowning group (right lung), drowning treated with PTX group and PTX alone group. At different time points after drowning, the changes of hemodynamic parameters and wet/dry weight of indirect lung (left lung) tissues were compared among these 4 groups. Other measures included lung histopathology, PMN infiltration assessed by immune staining, CD11b, ICAM-1 mRNA and TNF-alphamRNA in left lung detected by RT-PCR. NF-kappaB activation in blood neutrophils and lungs were measured with electrophoretic mobility shift assay (EMSA). RESULTS: Animals treated with PTX showed a significant reduction in lung injury. PTX suppressed drowning-induced ICAM-1 and TNF-alphamRNA elevation and inhibited NF-kappaB activation in blood neutrophils and lungs. CONCLUSIONS: Continuous infusion of PTX reduces ILI caused by fresh water drowning. PTX decreases expression of ICAM-1 and TNF-alpha, possibly via inhibition of NF-kappaB.
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Afogamento , Pulmão/efeitos dos fármacos , Pentoxifilina/farmacologia , Animais , Sequência de Bases , Antígeno CD11b/metabolismo , Primers do DNA , Cães , Ensaio de Desvio de Mobilidade Eletroforética , Molécula 1 de Adesão Intercelular/genética , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar , Masculino , NF-kappa B/metabolismo , Neutrófilos/citologia , Tamanho do Órgão , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/genéticaRESUMO
The effects of graded doses of pentoxifylline (PTX) on endotoxin-induced production of inflammatory cytokines and activation of nuclear factor kappa B (NF-kappaB) were studied in vivo in rat intestine. Sepsis was induced in rats by ip injection of lipopolysaccharide (LPS, 5 mg/kg). PTX was injected via the tail vein at dosages of 6.25, 12.5, 25, 50, or 100 mg/kg at 1 min after LPS challenge. NF-kappaB activation in intestine was investigated by electrophoretic mobility shift assay (EMSA). Tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-10 (IL-10) levels were measured in intestine by enzyme-linked immunosorbance assays (ELISA). Intestinal TNF-alpha, IL-6, and IL-10 mRNA expression were studied by the reverse-transcription polymerase chain reaction (RT-PCR). The measurements of NF-kappaB, TNF-alpha, IL-6, and IL-10 were performed, respectively, at 1, 4, 4, and 1 hr after endotoxin injection. The results showed that LPS elevated the production of TNF-alpha, IL-6, and IL-10 and enhanced NF-kappaB activation in rat intestine. At all dosages, PTX reduced the activation of NF-kappaB and the production of TNF-alpha and IL-6, but enhanced the release of IL-10. These effects were greatest at dosages of 50 mg/kg for TNF-alpha and IL-6, and 25 mg/kg for IL-10. In conclusion, PTX suppressed the production of proinflammatory cytokines such as TNF-alpha and IL-6 in rat intestine, and enhanced the endotoxin-induced production of IL-10. The suppressive effect of proinflammatory cytokines may act by inhibiting NF-kappaB activation, but not by induction of IL-10.