Synthesis of 1,4‐Anthracene‐9,10‐dione Derivatives and Their Regulation of Nitric Oxide,IL‐1β and TNF‐α in Activated RAW264.7 Cells

Mitoxantrone is an anthracenedione antineoplastic and immunosuppressive agent approved for multiple sclerosis treatment. Novel mono‐ and disubstituted anthraquinone derivatives, analogues of mitoxantrone, were synthesized through the addition of lipophilic amino alcohols and evaluated for their effect on IL‐1β, TNF‐α and nitric oxide production by LPS/IFN‐γ‐stimulated RAW264.7 cells. The disubstituted 1,4‐anthracene‐9,10‐dione 10 showed significant inhibition of nitric oxide, TNF‐α and IL‐1β production at the concentration of 5 μg/mL, with a much lower cytotoxicity than mitoxantrone. The monosubstituted 3 , 4 , 11, 12 and 13 also displayed a moderate to good inhibitory capacity on IL‐1β production. However, the methylated compounds 11, 12 and 13 failed to inhibit the TNF‐α production, and compound 13 was the only one to decrease the production of nitric oxide. None of these derivatives was toxic at the tested concentrations. Compounds 10 and 13 had better inhibitory capacity of the inflammatory mediators analyzed, with reliable viability of the cells.     

Acute effect of β‐sitosterol on calcium uptake mediates anti‐inflammatory effect in murine activated neutrophils

Objectives To evaluate the effect of β‐sitosterol on ⁴⁵Ca²⁺ uptake in activated murine neutrophils, and upon myeloperoxidase and adenosine deaminase activity, and interleukin‐1β (IL‐1β) and tumour necrosis factor‐α (TNF‐α) levels, in carrageenan‐induced inflammation in the mouse air pouch model. Methods Dried Esenbeckia leiocarpa bark was macerated and extracted resulting in a crude hydroalcoholic extract (CHE) that was partitioned to obtain an alkaloid fraction. The alkaloid was then partitioned in polar and nonpolar subfractions. β‐Sitosterol was isolated from the nonpolar subfraction and identified by comparison with the literature. The effect of β‐sitosterol on ⁴⁵Ca²⁺ uptake in activated murine neutrophils, and upon myeloperoxidase and adenosine deaminase activity, IL‐1β and TNF‐α levels in carrageenan‐induced inflammation in mice were evaluated. Key findings β‐Sitosterol promoted a time‐ and dose‐dependent increase of the calcium uptake in activated neutrophils that was promptly reversed by nifedipine, BAPTA‐AM, LY294002, and colchicine. β‐Sitosterol inhibited myeloperoxidase and adenosine deaminase activity, and IL‐1β and TNF‐α levels. Conclusions β‐Sitosterol inhibited either myeloperoxidase and adenosine deaminase activity or IL‐1β and TNF‐α levels. This effect seemed to be mediated by the calcium uptake in activated neutrophils in a time‐ and concentration‐dependent manner through L‐type voltage dependent calcium channels, intracellular calcium, phosphoinositide kinase‐3, and microtubule modulation.     

Evaluation and in vivo efficacy study of pyrano[3,2‐c]quinoline analogues as TNF‐α inhibitors

A series of pyrano[3,2 c]quinoline was evaluated for its in vivo efficacy as TNF‐α inhibitor using LPS, phosphodiesterase (PDE)‐4, and CIA assays in different mice/rat models. The synthesis was performed using one‐pot multicomponent condensation between 2,4‐dihydroxy‐1‐methylquinoline, malononitrile, and diverse un(substituted) aromatic aldehydes. In vivo efficacy of the title compounds was evaluated using LPS assay in BALB/c mice, PDE4 inhibition in ketamine–xylazine‐induced anesthetize SD rats, and CIA assay was performed in DBA/1J mice as per the standard literature protocols. The outcome of the study revealed that compound 4v was found to be most promising candidate of the series. It was efficacious with 48.8 ± 13.0% inhibition of TNF‐α release at 100 mg/kg p.o., in the LPS assay in Balb/c mice model. It was effective in PDE4 assay in ketamine–xylazine‐induced anesthetize SD rats with duration of 38.3 ± 4.5 min for reversal of anesthetic effect and also showed significant inhibition of PDE4 in salbutamol treated U937 cell assay. It was also abolished TNF‐α induced phosphorylation and degradation of IκBα. Ultimately, its effect on CIA‐related bone and cartilage damage was found statistically similar to Enbrel.     

S1P facilitates IL‐1β production in osteoblasts via the JAK and STAT3 signaling pathways

Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease, in which the immune system attacks synovial joint tissues. Interleukin (IL)‐1β is a critical proinflammatory cytokine in RA progression. Sphingosine‐1‐phosphate (S1P), a platelet‐derived lysophospholipid mediator, reportedly regulates osteoimmunology. Here, we investigated how S1P mediates IL‐1β expression in osteoblasts. Our analysis of records from the Gene Expression Omnibus (GEO) database demonstrate higher levels of IL‐1β in patients with RA compared with those with osteoarthritis. Stimulation of osteoblasts with S1P concentration dependently increased mRNA and protein expression of IL‐1β. Elevations in IL‐1β mRNA expression induced by S1P were reduced by the small interfering RNA (siRNA) against the S1P₁ receptor. S1P also augmented JAK and STAT3 molecular cascades. We also found that JAK and STAT3 inhibitors and their siRNAs antagonized S1P‐promoted IL‐1β expression. Our results indicate that S1P promotes the expression of IL‐1β in osteoblasts via the S1P₁ receptor and the JAK and STAT3 signaling pathways.     

Dexmedetomidine preconditioning for myocardial protection in ischaemia‐reperfusion injury in rats by downregulation of the high mobility group box 1‐toll‐like receptor 4‐nuclear factor κB signalling pathway

Pharmacological preconditioning reduces myocardial infarct size in ischaemia‐reperfusion (I‐R) injury. Dexmedetomidine, a selective α₂‐adrenoceptor agonist, has a proven cardioprotective effect when administered prior to I‐R, although the underlying mechanisms for this effect are not fully understood. We evaluated whether dexmedetomidine preconditioning could induce a myocardio‐protective effect against I‐R injury by inhibiting associated inflammatory processes through downregulation of the high mobility group box 1 (HMGB1)‐toll‐like receptor 4 (TLR4)‐nuclear factor κB (NF‐κB) signalling pathway. Seventy rats were randomly assigned to seven groups: a control and six test groups, involving I‐R for 30 and 120 minutes, respectively, in isolated rat hearts and different pretreatment protocols with dexmedetomidine (10 nmol/L) as well as yohimbine (1 μmol/L) and recombinant HMGB1 peptide (rHMGB1; 20 μg/L), alone or in combination with dexmedetomidine. Cardiac function was recorded; myocardial HMGB1, TLR4, and NF‐κB activities and levels of tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) were measured as were lactate dehydrogenase (LDH) and creatine kinase (CK) in coronary outflow. Dexmedetomidine preconditioning significantly improved cardiac function (P<.05), downregulated the expression of HMGB1‐TLR4‐NF‐κB, reduced levels of TNF‐α and IL‐6 in isolated ventricles during I‐R injury, and significantly reduced CK and LDH levels in coronary outflow (P<.05). All of these effects were partially reversed by yohimbine (P<.05) or rHMGB1 (P<.05). Dexmedetomidine preconditioning alleviated myocardial I‐R injury in rats through inhibition of inflammatory processes associated with downregulation of the HMGB1‐TLR4‐NF‐κB signalling pathway via activation at α₂‐adrenergic receptors.     

Therapeutic index of methotrexate depends on circadian cycling of tumour necrosis factor‐α in collagen‐induced arthritic rats and mice

Objectives Rheumatoid arthritis is an autoimmune disorder of unknown aetiology. Morning stiffness, a characteristic feature of rheumatoid arthritis, shows a 24‐h rhythm. Noticing this rhythm, we hypothesized the presence of a similar rhythm for a rheumatoid arthritis indicator, in addition to dosing‐time dependency of the anti‐rheumatic effect of methotrexate in arthritis induced by collagen in rats and mice, which reflect the symptomatology of rheumatoid arthritis patients. Methods To measure tumour necrosis factor (TNF)‐α concentration, blood was taken at different times (2, 6, 10, 14, 18 or 22 h after the light was turned on (HALO)) in collagen‐induced arthritic mice. Methotrexate was administered at two different dosing times based on these findings to estimate arthritis. Key findings The arthritis score was significantly lower in the 22 HALO‐treated group than in the control and 10 HALO‐treated groups in collagen‐induced arthritic rats and mice. Plasma TNF‐α concentrations showed obvious 24‐h rhythms, with higher levels at light phase and lower levels at dark phase after rheumatoid arthritis crisis. Arthritis was relieved after administration of methotrexate during the dark phase in synchronization with the 24‐h rhythm. Conclusions Our findings suggest that choosing an optimal dosing time associated with the 24‐h cycling of TNF‐α could lead to effective treatment of rheumatoid arthritis by methotrexate.     

Inflammatory cytokines tumour necrosis factor‐α and interleukin‐8 enhance airway smooth muscle contraction by increasing L‐type Ca2+ channel expression

Inflammation elevates intracellular calcium concentrations ([Ca²⁺]_i) in airway smooth muscle (ASM). The L‐type Ca²⁺ channel (L‐VDCC) plays an important role in regulating Ca²⁺ influx in ASM. However, the role of L‐VDCC in the inflammatory cytokine‐induced pathology of ASM remains unclear. In the present study, we used calcium imaging and isometric tension measurements to assess the role of L‐VDCC in agonist‐induced [Ca²⁺]_i rise and the associated contractions in mouse ASM, and we used immunoblotting to identify L‐VDCC protein expression levels in mouse ASM after exposure to tumour necrosis factor alpha (TNF‐α) or interleukin‐8 (IL‐8). Our results showed that high‐K⁺‐ or carbachol‐induced contractions of mouse ASM were significantly greater after pretreatment with TNF‐α or IL‐8 for 24 hours. Both verapamil and nifedipine, L‐VDCC inhibitors, abolished this increased contraction induced by TNF‐α or IL‐8 pretreatment. Moreover, TNF‐α treatment enhanced carbachol‐induced Ca²⁺ influx in ASM cells, and this effect was abrogated by verapamil. Additionally, immunoblotting results showed that preincubation of mouse ASM with TNF‐α or IL‐8 also enhanced L‐VDCC protein expression. On the basis of these findings, we concluded that proinflammatory cytokines, such as TNF‐α and IL‐8, increase the expression level of L‐VDCC, which in turn contributes to augmented agonist‐induced ASM contractions. This effect of inflammation on L‐VDCC expression in ASM may be associated with airway hyper‐responsiveness and involved in the development of asthma.     

Antihypertensive methyldopa,labetalol, hydralazine,and clonidine reversed tumour necrosis factor‐α inhibited endothelial nitric oxide synthase expression in endothelial‐trophoblast cellular networks

Medications used to control hypertension in pregnancy also improve trophoblast and endothelial cellular interaction in vitro. Tumour necrosis factor‐α (TNF‐α) inhibits trophoblast and endothelial cellular interactions and simultaneously decreases endothelial nitric oxide synthase (eNOS) expression. This study investigated whether antihypertensive medications improved these cellular interactions by modulating eNOS and inducible nitric oxide synthase (iNOS) expression. Human uterine myometrial microvascular endothelial cells (UtMVECs) were pre‐incubated with (or without) low dose TNF‐α (0.5 ng/mL) or TNF‐α plus soluble fms‐like tyrosine kinase‐1 (sFlt‐1) (100 ng/mL). The endothelial cells were cultured on Matrigel. After endothelial cellular networks appeared, trophoblast derived HTR‐8/SVneo cells were co‐cultured in the presence of clinically relevant doses of methyldopa, labetalol, hydralazine or clonidine for 24 hours. Cells were retrieved from the Matrigel to extract mRNA and eNOS and iNOS expression were examined by quantitative PCR. Methyldopa, labetalol, hydralazine and clonidine reversed the inhibitory effect of TNF‐α on eNOS mRNA expression. After pre‐incubating endothelial cells with TNF‐α and sFlt‐1, all the medications except methyldopa lost their effect on eNOS mRNA expression. In the absence of TNF‐α, antihypertensive medications did not change eNOS expression. The mRNA expression of iNOS was not affected by TNF‐α or any medications. This study shows that selected antihypertensive medications used in the treatment of hypertension in pregnancy increase eNOS expression in vitro when induced by the inflammatory TNF‐α. The anti‐angiogenic molecule sFlt‐1 may antagonise the potential benefit of these medications by interfering with the NOS pathway.     

5‐Amino‐3‐methyl‐4‐isoxazolecarboxylic acid hydrazide derivatives with in vitro immunomodulatory activities

Isoxazoles are an important class of compounds of potential therapeutic value. The aim of this study was to determine immunotropic effects of 5‐amino‐3‐methyl‐4‐isoxazolecarboxylic acid hydrazide derivatives on spontaneous and mitogen‐induced lymphocyte proliferation in young and old mice, cytokine production by peritoneal cells as well as possible mechanism of action in a model of Jurkat cells. Three‐month‐old and 13‐month‐old BALB/c mice were used as donors of the cells from a thymus, a spleen, mesenteric lymph nodes, and a peritoneal cavity. Spontaneous and concanavalin A or lipopolysaccharide (LPS)‐induced cell proliferation was measured by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide colorimetric method. IL‐1β and TNF‐α production induced by LPS in macrophage‐enriched peritoneal cell cultures was measured by enzyme‐linked immunoassay. 5‐amino‐3‐methyl‐4‐isoxazolecarboxylic acid hydrazide, 01K (4‐phenyl‐1‐(5‐amino‐3‐methylisoxazole‐4‐carbonyl)‐thiosemicarbazide), and 06K (4‐(4‐chlorophenyl)‐1‐(5‐amino‐3‐methylisoxazole‐4‐carbonyl)‐thiosemicarbazide) exhibited regulatory activity in the proliferation tests. Prevailing stimulatory activity of the hydrazide and inhibitory activity of 01K and 06K was observed. Those effects were connected with different influence of the compounds on signaling proteins expression in Jurkat cells. The regulatory effects of the compounds on IL‐1β production were more profound than those on TNF‐α. Differences in the compound activity in young versus old mice were mainly restricted to 01K. Immunosuppressive isoxazole leflunomide and a stimulatory RM‐11 (1,7‐dimethyl‐8‐oxo‐1,2H‐isoxazole [5,4‐e]triazepine) were applied as reference drugs.     

Glucose suppresses IL‐1β‐induced MMP‐1 expression through the FAK,MEK, ERK,and AP‐1 signaling pathways

Osteoarthritis (OA) commonly affects the synovial joint and is characterized by degradation of articular cartilage. Increased matrix metalloproteinase (MMP) activity plays a major role in this degradation. Dextrose (D‐glucose) prolotherapy has shown promising activity in the treatment of different musculoskeletal disorders, including OA. However, little is known about the role of glucose on MMP inhibition in OA therapy. We found that stimulating chondrocytes with the proinflammatory cytokine interleukin‐1β (IL‐1β) increased the expression of MMP‐1, MMP‐3, and MMP‐13. Glucose reduced this increase in MMP‐1 expression, but had no effect upon MMP‐3 or MMP‐13 expression. Analyses using a focal adhesion kinase (FAK) inhibitor, MEK inhibitors (U0126 and PD98059), an ERK inhibitor, AP‐1 inhibitors (curcumin and tanshinone), or siRNAs demonstrated that the FAK, MEK, ERK, and AP‐1 pathways mediate IL‐1β‐induced increases in MMP‐1 expression. Glucose antagonized IL‐1β‐promoted phosphorylation of FAK, MEK, ERK, and c‐Jun. Thus, glucose decreased IL‐1β‐induced MMP‐1 expression through the FAK, MEK, ERK, and AP‐1 signaling cascades. These findings may provide a better understanding of the mechanisms of prolotherapy on inhibiting MMP expression.     

β‐asarone and levodopa co‐administration protects against 6‐hydroxydopamine‐induced damage in parkinsonian rat mesencephalon by regulating autophagy: down‐expression Beclin‐1 and light chain 3B and up‐expression P62

In this study, we investigated Beclin‐1, light chain (LC)3B, and p62 expression in 6‐hydroxydopamine (6‐OHDA)‐induced parkinsonian rats after β‐asarone and levodopa (l ‐dopa) co‐administration. Unilateral 6‐OHDA injection into the medial forebrain bundle was used to create the models, except in sham‐operated rats. Rats were divided into eight groups: sham‐operated group; 6‐OHDA model group; madopar group (75 mg/kg, per os (p.o.)); l ‐dopa group (60 mg/kg, p.o.); β‐asarone group (15 mg/kg, p.o.); β‐asarone + l ‐dopa co‐administered group (15 mg/kg + 60 mg/kg, p.o.); 3‐methyladenine group (500 nmol, intraperitoneal injection); and rapamycin group (1 mg/kg, intraperitoneal injection). Then, Beclin‐1, LC3B, and p62 expression in the mesencephalon were detected. The mesencephalon was also observed by transmission electron microscope. The results showed that Beclin‐1 and LC3B expression decreased and that p62 expression increased significantly in the madopar, l ‐dopa, β‐asarone, and co‐administered groups when compared with the 6‐OHDA model. Beclin‐1 and LC3B expression in the β‐asarone and co‐administered groups were less than in the madopar or l ‐dopa groups, whereas p62 expression in the β‐asarone and co‐administered groups was higher than in the madopar or l ‐dopa groups. In addition, a significant decrease in autophagosome was exhibited in the β‐asarone and co‐administered groups when compared with the 6‐OHDA group. Our findings indicate that Beclin‐1 and LC3B expression decreased, whereas p62 expression increased after co‐administration treatment. In sum, all data suggest that the co‐administration of β‐asarone and l ‐dopa may contribute to the treatment of 6‐OHDA‐induced damage in rats by inhibiting autophagy activity.     

Size‐dependent superparamagnetic iron oxide nanoparticles dictate interleukin‐1β release from mouse bone marrow‐derived macrophages

Superparamagnetic iron oxide nanoparticles (SPIONs) have been widely investigated for their biomedical applications in magnetic resonance imaging, targeting therapy, cell labeling, etc. It has been well documented that macrophages produce interleukin (IL)‐1β via several signaling pathways, such as inflammasome activation in response to particles including silica, asbestos and urea crystals with lipopolysaccharide priming. However, the size and dose effects of SPIONs on macrophages and the mechanisms remain unclear. In this study, we explored the cytotoxicity and mechanisms of the synthesized SPIONs with different size distributions of 30, 80 and 120 nm, and compared their potential capability in inducing IL‐1β release in mouse bone marrow‐derived macrophages (BMMs). We found that SPIONs induced IL‐1β release in a size‐ and dose‐dependent manner, in which the smallest SPIONs triggered the highest IL‐1β in BMMs. When cellular uptake of SPIONs was inhibited by the actin polymerization inhibitor, cytochalasin D, SPION‐induced IL‐1β release was suppressed in BMMs. Preventing lysosome damage with bafilomycin A1 or CA‐074‐Me also counteracted SPION‐induced IL‐1β release. Moreover, SPION‐activated IL‐1β release was also attenuated by reactive oxygen species scavengers, diphenylene iodonium or N‐acetylcysteine. Our results elucidated the effects of size and dose on the cytotoxicity and mechanisms of IL‐1β release of SPIONs on macrophages, which facilitate the theoretical and experimental application of SPIONs in biotechnology and biomedicine in the future.     

β‐LAPachone ameliorates doxorubicin‐induced cardiotoxicity via regulating autophagy and Nrf2 signalling pathways in mice

β‐LAPachone (B‐LAP) is a naphthoquinone that possesses antioxidant properties. In the present investigation, the protective effect of B‐LAP against doxorubicin (DOX)‐induced cardiotoxicity was examined in mice. Thirty‐five mice were divided into 5 groups: control group, B‐LAP (5 mg/kg) group, DOX (15 mg/kg) group, DOX+B‐LAP (2.5 mg/kg) group and DOX+B‐LAP (5 mg/kg) group. B‐LAP was administered orally for 14 days of experimental period. A single dose of DOX (15 mg/kg) was injected intraperitoneally on day 3. Cardiac function, histoarchitecture, indices of oxidative stress and circulating markers of cardiac injury were examined. B‐LAP (5 mg/kg) decreased serum levels of lactate dehydrogenase (LDH), creatine kinase MB (CK‐MB) and cardiac troponin I (cTnI), and ameliorated cardiac histopathological alterations. In addition to increasing cellular NAD⁺/NADH ratio, B‐LAP up‐regulated the cardiac levels of SIRT1, beclin‐1, p‐LKB1 and p‐AMPK, and reduced the cardiac levels of p‐mTOR, interleukin (IL)‐1β, TNF (tumour necrosis factor)‐α and caspase‐3. B‐LAP also elevated the nuclear accumulation of Nrf2 and simultaneously up‐regulated the protein levels of haem oxygenase (HO‐1) and glutathione S‐transferase (GST) in the hearts of DOX mice. While B‐LAP reduced malondialdehyde concentrations in heart of DOX‐treated mice, it further promoted the activities of cardiac superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT).In accordance with increased cell survival, B‐LAP significantly improved the cardiac function of DOX mice. Collectively, these findings underline the protective potential of B‐LAP against DOX‐induced cardiotoxicity by regulating autophagy and AMPK/Nrf2 signalling pathway in mice.     

Surgery‐induced changes in rat IL‐1β and acetylcholine metabolism: role of physostigmine

Pharmacological enhancement of cholinergic activity following administration of physostigmine is known to induce protective effects generally. However, it is unclear whether the effect of physostigmine on inflammation and acetylcholine (ACh) metabolism is related to different types of surgical intervention or anaesthesia alone. To investigate this, rats were subjected to partial liver resection (PLR) or sham surgery, with a control group receiving anaesthesia alone. Half of each treatment group received a single intra‐operative dose of physostigmine (0.04 mg/kg); the others received placebo. Acetylcholinesterase (AChE) activity and plasma and brain concentrations of interleukin (IL)‐1β and ACh were determined. Both PLR and sham operation induced a time‐dependent increase in plasma concentrations of IL‐1β compared with rats receiving anaesthesia alone (3.9‐ and 4.8‐fold increases, respectively). In the brain, IL‐1β concentrations had increased approximately twofold after surgery compared with the control group. Blood AChE was transiently decreased after surgery. Brain AChE activity increased 1.3‐fold (P = 0.014) only after PLR; consequently, cerebral ACh concentrations were significantly reduced. Physostigmine administration significantly reduced IL‐1β and AChE levels. Cerebral ACh concentrations were markedly increased from 544 ± 122 ng/mg protein following placebo administration to 654 ± 93 ng/mg protein after physostigmine administrations (P < 0.001). We conclude that a single dose of physostigmine intra‐operatively has a sustained anti‐inflammatory effect (up to 120 min after injection) that is especially pronounced under the conditions of PLR surgery. In addition to its protective peripheral action, physostigmine exerts a neuroprotective action by increasing levels of the neurotransmitter ACh.     

Discovery of naphthyl‐N‐acylhydrazone p38α MAPK inhibitors with in vivo anti‐inflammatory and anti‐TNF‐α activity

Protein kinases constitute attractive therapeutic targets for development of new prototypes to treat different chronic diseases. Several available drugs, like tinibs, are tyrosine kinase inhibitors; meanwhile, inhibitors of serine/threonine kinases, such as mitogen‐activated protein kinase (MAPK), are still trying to overcome some problems in one of the steps of clinical development to become drugs. So, here we reported the synthesis, the in vitro kinase inhibitory profile, docking studies, and the evaluation of anti‐inflammatory profile of new naphthyl‐N‐acylhydrazone derivatives using animal models. Although all tested compounds ( 3a–d ) have been characterized as p38α MAPK inhibitors and have showed in vivo anti‐inflammatory action, LASSBio‐1824 ( 3b ) presented the best performance as p38α MAPK inhibitor, with IC₅₀ = 4.45 μm , and also demonstrated to be the most promising anti‐inflammatory prototype, with good in vivo anti‐TNF‐α profile after oral administration.     

Exposures to the environmental contaminants pentachlorophenol and dichlorodiphenyltrichloroethane increase production of the proinflammatory cytokine,interleukin‐1β, in human immune cells

Pentachlorophenol (PCP) and dichlorodiphenyltrichloroethane (DDT) are organochlorine environmental contaminants found in human blood at very significant levels (as high as 5 μm for PCP and 260 nm for DDT). Cancers of the blood (lymphoma and myeloma) and kidney as well as others have been associated with exposure to these contaminants. Interleukin (IL)‐1β is a proinflammatory cytokine and is involved in stimulating cell proliferation. High levels of IL‐1β are associated with inflammatory diseases and tumor progression. Previous studies showed that PCP and DDT at certain concentrations were able to stimulate secretion of IL‐1β. This study shows that the increased secretion of IL‐1β seen with both contaminants is due to compound‐induced increases in the production of this cytokine. Increased production began within 6 hours of exposure to PCP and continued to increase up to 24 hours. DDT‐induced stimulation of IL‐1β appeared to be maximal after 6 hours of exposure and then diminished by 24 hours. The increases seen in IL‐1β production stimulated by PCP appear to be at least partially due to compound‐induced increases in IL‐1β mRNA. Although DDT caused increased production of IL‐1β, it did not appear to cause consistent increases in its mRNA. PCP‐ and DDT‐induced increases in IL‐1β production were dependent primarily on the p38 mitogen‐activated protein kinase pathway. These results indicate that both PCP and DDT are able to increase IL‐1β production in a p38 mitogen‐activated protein kinase‐dependent manner, which may have the potential to influence chronic inflammation.