Modulation of inflammatory responses by Sutherlandia frutescens

Sutherlandia frutescens (L.) R. Br (Lessertia frutescens) is a medicinal plant traditionally used in southern Africa. It has been used for patients suffering from numerous types of cancer, infectious diseases, and various inflammatory conditions. This study was designed to determine the impact of S. frutescens on the inflammatory response and anti-microbial activities on cell and/or animal models. Aqueous and ethanolic extracts of S. frutescens were made and verified using HPLC. These extracts were used to treat murine macrophages (e.g., RAW 264.7 cells and primary macrophages isolated from mice) to evaluate the impact of S. frutescens on in vitro inflammatory responses. This study found that the aqueous extract and a polysaccharide-enriched fraction from the aqueous extract exhibited an immuno-stimulatory activity on murine macrophages. Treatment with aqueous extract or polysaccharides increased the production of reactive oxygen species (ROS), nitric oxide (NO), and inflammatory cytokines/chemokines via activating the toll-like receptor 4 signaling pathway. On the other hand, the ethanolic extract of S. frutescens dose-dependently decreased the production of ROS, NO, inducible nitric oxide synthase (iNOS), and various inflammatory cytokines and chemokines in murine macrophages co-stimulated with lipopolysaccharide (LPS) and interferon gamma (IFNy). Follow up experiments demonstrated that the anti-inflammatory activity of the ethanolic extract was mediated via reductions in the activation of NF-kB, extracellular-signal-regulated kinase 1/2 (ERK1/2), and signal transducers and activators of transcription 1 (STAT1). RNA sequencing provided more evidences to support the anti-inflammatory activity of the ethanolic extract of S. frutescens. To our surprise, chlorophylls isolated from S. frutescens had a greater effect on the anti-inflammatory of S. frutescens than that of unique compounds (i.e., sutherlandiosides and sutherlandins). To investigate the impact of oral consumption of S. frutescens on in vivo inflammatory responses and anti-microbial activities, mice were fed with AIN-93G based diet with/without containing ground S. frutescens powder or were gavaged with S. frutescens extracts followed by challenge with E. coli or LPS. These experiments found that oral consumption of S. frutescens had limited or no impact on the in vivo inflammatory responses and anti-microbial activities. Overall, this study provide a better understanding on the beneficial therapeutic properties of S. frutescens using in vitro models, however these studies in a laboratory mouse model suggest that consumption of S. frutescens had only a modest impact on host anti-microbial and inflammatory responses to a gram-negative microbial challenge whether intact microbes or bacterial endotoxin (i.e., LPS) was used.

Gain-of-Function Mutation of Tristetraprolin Impairs Negative Feedback Control of Macrophages In Vitro yet Has Overwhelmingly Anti-Inflammatory Consequences In Vivo

Molecular and Cellular Biology ◽

10.1128/mcb.00536-16 ◽

2017 ◽

Vol 37 (11) ◽

Cited By ~ 3

Author(s):

John D. O'Neil ◽

Ewan A. Ross ◽

Michael L. Ridley ◽

Qize Ding ◽

Tina Tang ◽

...

Keyword(s):

Feedback Control ◽

Negative Feedback ◽

Inflammatory Responses ◽

Interleukin 10 ◽

Gain Of Function ◽

Negative Feedback Control ◽

Anti Inflammatory ◽

ABSTRACT The mRNA-destabilizing factor tristetraprolin (TTP) binds in a sequence-specific manner to the 3′ untranslated regions of many proinflammatory mRNAs and recruits complexes of nucleases to promote rapid mRNA turnover. Mice lacking TTP develop a severe, spontaneous inflammatory syndrome characterized by the overexpression of tumor necrosis factor and other inflammatory mediators. However, TTP also employs the same mechanism to inhibit the expression of the potent anti-inflammatory cytokine interleukin 10 (IL-10). Perturbation of TTP function may therefore have mixed effects on inflammatory responses, either increasing or decreasing the expression of proinflammatory factors via direct or indirect mechanisms. We recently described a knock-in mouse strain in which the substitution of 2 amino acids of the endogenous TTP protein renders it constitutively active as an mRNA-destabilizing factor. Here we investigate the impact on the IL-10-mediated anti-inflammatory response. It is shown that the gain-of-function mutation of TTP impairs IL-10-mediated negative feedback control of macrophage function in vitro. However, the in vivo effects of TTP mutation are uniformly anti-inflammatory despite the decreased expression of IL-10.

In Vivo and in Vitro Anti-Inflammatory Activities of Extracts of Pandiaka angustifolia (Vahl.) Hepper (Amaranthaceae) Used in Traditional Medicine in Burkina Faso

Academic Journal of Life Sciences ◽

10.32861/ajls.68.101.107 ◽

2020 ◽

pp. 101-107

Author(s):

Emmanuel A. M. Thiombiano ◽

Mindiédiba Jean Bangou ◽

Yougbaré-Ziébrou Mouhibatou ◽

Martin Kiendrebeogo

Keyword(s):

Aqueous Extract ◽

Analgesic Activity ◽

Ethanolic Extract ◽

Scientific Basis ◽

Hexane Extract ◽

K Channel ◽

Aqueous Extracts ◽

Background: Pandiaka angustifolia Valh Hepper (Amaranthaceae) whole plant is used in folk Burkinabe’s medicine to treat ailments with an inflammatory component. Previous studies revealed the antioxidant capacity, xanthine oxidase, and lipoxygenase inhibitory activities of the plant, but to the best of our knowledge, its anti-inflammatory activities were not reported before. Therefore, this study was designed to evaluate the anti-inflammatory and analgesic activity of P. Angustifolia hexane and aqueous extracts using in vitro enzymatic methods and in vivo methods and verify the best anti-inflammatory extract implication in KATP pathways. Experiments: acute toxicity of the plant was conducted under OECD 423 guidelines. Phospholipase and cyclooxygenases were pro-inflammatory enzymes used to evaluate in vitro anti-inflammatory effects of plant extracts while carrageenan induced edema method was used to evaluate the anti-edematous activity and acetic acid inducing writhing method to evaluate the non-morphine analgesic effect of herbal mixture. ATP sensitive K+ channel assay was performed in vivo using the glibenclamide as ATP-sensitive potassium channel (KATP) blocker. Results: enzymatic inhibition assays revealed that both hexane and aqueous extracts of P. angustifolia were good inhibitors against sPLA2 activity with IC50 values of 14.23 ± 0. 72 µg/mL and 11.56 ± 0.11 µg/mL, respectively. Aqueous extract presented the best inhibition for COX-1 (IC50 = 24.76 ±0. 51 µg/mL) while hexane extract concentration that inhibit 50% of COX-2 was lesser than those of aqueous extract. P. angustifolia aqueous extract orally administrated to NMRI mice caused no death at the dose of 3000 mg/kg b.w indicating that the plant toxicity is low. While hexane extract was unable to reduce Carrageenan-induced edema, ethanolic extract were significantly active when extract was orally administrated. Non-morphine analgesic activity evaluation revealed that ethanolic extract was more efficient on writhing reduction than hexane extract. Nociception effect of the plant is linked with its effects on K+ ATP sensitive channels. Conclusion: Results indicate that the anti-inflammatory potential of P. angustifolia may be due to its polar phytoconstituents and observed pharmacological activities provide the scientific basis for the medicinal use of the plant in the treatment of ailment associated with inflammation.

The impact of indole-3-lactic acid on immature intestinal innate immunity and development: a transcriptomic analysis

Scientific Reports ◽

10.1038/s41598-021-87353-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Wuyang Huang ◽

Ky Young Cho ◽

Di Meng ◽

W. Allan Walker

Keyword(s):

Lactic Acid ◽

Mechanistic Model ◽

Transcriptomic Analysis ◽

Dependent Manner ◽

Protective Effects ◽

Very Preterm Infants ◽

Anti Inflammatory ◽

AbstractAn excessive intestinal inflammatory response may have a role in the pathogenesis of necrotizing enterocolitis (NEC) in very preterm infants. Indole-3-lactic acid (ILA) of breastmilk tryptophan was identified as the anti-inflammatory metabolite involved in probiotic conditioned media from Bifidobacteria longum subsp infantis. This study aimed to explore the molecular endocytic pathways involved in the protective ILA effect against inflammation. H4 cells, Caco-2 cells, C57BL/6 pup and adult mice were used to compare the anti-inflammatory mechanisms between immature and mature enterocytes in vitro and in vivo. The results show that ILA has pleiotropic protective effects on immature enterocytes including anti-inflammatory, anti-viral, and developmental regulatory potentials in a region-dependent and an age-dependent manner. Quantitative transcriptomic analysis revealed a new mechanistic model in which STAT1 pathways play an important role in IL-1β-induced inflammation and ILA has a regulatory effect on STAT1 pathways. These studies were validated by real-time RT-qPCR and STAT1 inhibitor experiments. Different protective reactions of ILA between immature and mature enterocytes indicated that ILA’s effects are developmentally regulated. These findings may be helpful in preventing NEC for premature infants.

In Vitro Evaluation of the Anti-Inflammatory Effect of KMUP-1 and in Vivo Analysis of Its Therapeutic Potential in Osteoarthritis

Biomedicines ◽

10.3390/biomedicines9060615 ◽

2021 ◽

Vol 9 (6) ◽

pp. 615

Author(s):

Shang-En Huang ◽

Erna Sulistyowati ◽

Yu-Ying Chao ◽

Bin-Nan Wu ◽

Zen-Kong Dai ◽

...

Keyword(s):

Articular Cartilage ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Antioxidant Properties ◽

Serum Levels ◽

Gene Expressions ◽

Tnf Α ◽

Osteoarthritis is a degenerative arthropathy that is mainly characterized by dysregulation of inflammatory responses. KMUP-1, a derived chemical synthetic of xanthine, has been shown to have anti-inflammatory and antioxidant properties. Here, we aimed to investigate the in vitro anti-inflammatory and in vivo anti-osteoarthritis effects of KMUP-1. Protein and gene expressions of inflammation markers were determined by ELISA, Western blotting and microarray, respectively. RAW264.7 mouse macrophages were cultured and pretreated with KMUP-1 (1, 5, 10 μM). The productions of TNF-α, IL-6, MMP-2 and MMP- 9 were reduced by KMUP-1 pretreatment in LPS-induced inflammation of RAW264.7 cells. The expressions of iNOS, TNF-α, COX-2, MMP-2 and MMP-9 were also inhibited by KMUP-1 pretreatment. The gene expression levels of TNF and COX families were also downregulated. In addition, KMUP-1 suppressed the activations of ERK, JNK and p38 as well as phosphorylation of IκBα/NF-κB signaling pathways. Furthermore, SIRT1 inhibitor attenuated the inhibitory effect of KMUP-1 in LPS-induced NF-κB activation. In vivo study showed that KMUP-1 reduced mechanical hyperalgesia in monoiodoacetic acid (MIA)-induced rats OA. Additionally, KMUP-1 pretreatment reduced the serum levels of TNF-α and IL-6 in MIA-injected rats. Moreover, macroscopic and histological observation showed that KMUP-1 reduced articular cartilage erosion in rats. Our results demonstrated that KMUP-1 inhibited the inflammatory responses and restored SIRT1 in vitro, alleviated joint-related pain and cartilage destruction in vivo. Taken together, KMUP-1 has the potential to improve MIA-induced articular cartilage degradation by inhibiting the levels and expression of inflammatory mediators suggesting that KMUP-1 might be a potential therapeutic agent for OA.

A sand fly salivary protein acts as a neutrophil chemoattractant

Nature Communications ◽

10.1038/s41467-021-23002-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Anderson B. Guimaraes-Costa ◽

John P. Shannon ◽

Ingrid Waclawiak ◽

Jullyanna Oliveira ◽

Claudio Meneses ◽

...

Keyword(s):

Inflammatory Responses ◽

Calcium Influx ◽

Parasite Burden ◽

Salivary Protein ◽

Sand Fly ◽

Human Neutrophils ◽

Chemotactic Protein ◽

AbstractApart from bacterial formyl peptides or viral chemokine mimicry, a non-vertebrate or insect protein that directly attracts mammalian innate cells such as neutrophils has not been molecularly characterized. Here, we show that members of sand fly yellow salivary proteins induce in vitro chemotaxis of mouse, canine and human neutrophils in transwell migration or EZ-TAXIScan assays. We demonstrate murine neutrophil recruitment in vivo using flow cytometry and two-photon intravital microscopy in Lysozyme-M-eGFP transgenic mice. We establish that the structure of this ~ 45 kDa neutrophil chemotactic protein does not resemble that of known chemokines. This chemoattractant acts through a G-protein-coupled receptor and is dependent on calcium influx. Of significance, this chemoattractant protein enhances lesion pathology (P < 0.0001) and increases parasite burden (P < 0.001) in mice upon co-injection with Leishmania parasites, underlining the impact of the sand fly salivary yellow proteins on disease outcome. These findings show that some arthropod vector-derived factors, such as this chemotactic salivary protein, activate rather than inhibit the host innate immune response, and that pathogens take advantage of these inflammatory responses to establish in the host.

Ellagitannins, Gallotannins and their Metabolites- The Contribution to the Anti-Inflammatory Effect of Food Products and Medicinal Plants

Current Medicinal Chemistry ◽

10.2174/0929867323666160919111559 ◽

2019 ◽

Vol 25 (37) ◽

pp. 4946-4967 ◽

Cited By ~ 18

Author(s):

Anna K. Kiss ◽

Jakub P. Piwowarski

Keyword(s):

Immune Response ◽

Gastrointestinal Tract ◽

Gut Microbiota ◽

Health Effects ◽

Biological Effects ◽

Food Products ◽

Anti Inflammatory ◽

The popularity of food products and medicinal plant materials containing hydrolysable tannins (HT) is nowadays rapidly increasing. Among various health effects attributable to the products of plant origin rich in gallotannins and/or ellagitannins the most often underlined is the beneficial influence on diseases possessing inflammatory background. Results of clinical, interventional and animal in vivo studies clearly indicate the antiinflammatory potential of HT-containing products, as well as pure ellagitannins and gallotannins. In recent years a great emphasis has been put on the consideration of metabolism and bioavailability of natural products during examination of their biological effects. Conducted in vivo and in vitro studies of polyphenols metabolism put a new light on this issue and indicate the gut microbiota to play a crucial role in the health effects following their oral administration. The aim of the review is to summarize the knowledge about HT-containing products’ phytochemistry and their anti-inflammatory effects together with discussion of the data about observed biological activities with regards to the current concepts on the HTs’ bioavailability and metabolism. Orally administered HT-containing products due to the limited bioavailability of ellagitannins and gallotannins can influence immune response at the level of gastrointestinal tract as well as express modulating effects on the gut microbiota composition. However, due to the chemical changes being a result of their transit through gastrointestinal tract, comprising of hydrolysis and gut microbiota metabolism, the activity of produced metabolites has to be taken into consideration. Studies regarding biological effects of the HTs’ metabolites, in particular urolithins, indicate their strong and structure-dependent anti-inflammatory activities, being observed at the concentrations, which fit the range of their established bioavailability. The impact of HTs on inflammatory processes has been well established on various in vivo and in vitro models, while influence of microbiota metabolites on silencing the immune response gives a new perspective on understanding anti-inflammatory effects attributed to HT containing products, especially their postulated effectiveness in inflammatory bowel diseases (IBD) and cardiovascular diseases.

Abstract 116: Slit-Robo Signaling Regulates Lipopolysaccharide-induced Endothelial Inflammation and Expression of Slit/Robo is Dysregulated During Endotoxemia

Circulation Research ◽

10.1161/res.113.suppl_1.a116 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Helong Zhao ◽

Appakkudal Anand ◽

Ramesh Ganju

Keyword(s):

Endothelial Cells ◽

Cell Adhesion ◽

Inflammatory Responses ◽

Umbilical Vein ◽

Model Studies ◽

Endothelial Inflammation ◽

Anti Inflammatory ◽

Whole Heart

Abstract Introduction: Lipopolysaccharide (LPS) is one of the critical factors which induce endothelial inflammation during the pathogenesis of atherosclerosis, endocarditis and sepsis shock induced heart injury. The secretory Slit2 protein and its endothelial receptors Robo1 and Robo4 have been shown to regulate mobility and permeability of endothelial cells, which could be functional in regulating LPS induced endothelial inflammation. Hypothesis: We hypothesized that in addition to regulating permeability and migration of endothelial cells, Slit2-Robo1/4 signaling might regulate other LPS-induced endothelial inflammatory responses. Methods and Results: Using Human Umbilical Vein Endothelial Cells (HUVEC) culture, we observed that Slit2 treatment suppressed LPS-induced secretion of pro-inflammatory cytokines (including GM-CSF), cell adhesion molecule upregulation and monocyte (THP-1 cell) adhesion. With siRNA knock down techniques, we further confirmed that this anti-inflammatory effect is mediated by the interaction of Slit2 with its dominant receptor in endothelial cells, Robo4, though the much lesser expressed minor receptor Robo1 is pro-inflammatory. Our signaling studies showed that downstream of Robo4, Slit2 suppressed inflammatory gene expression by inhibiting the Pyk2 - NF-kB pathway following LPS-TLR4 interaction. In addition, Slit2 can induce a positive feedback to its expression and downregulate the pro-inflammatory Robo1 receptor via mediation of miR-218. Moreover, both in in vitro studies using HUVEC and in vivo mouse model studies indicated that LPS also causes endothelial inflammation by downregulating the anti-inflammatory Slit2 and Robo4 and upregulating the pro-inflammatory Robo1 during endotoxemia, especially in mouse arterial endothelial cells and whole heart. Conclusions: Slit2-Robo1/4 signaling is important in regulation of LPS induced endothelial inflammation, and LPS in turn causes inflammation by interfering with the expression of Slit2, Robo1 and Robo4. This implies that Slit2-Robo1/4 is a key regulator of endothelial inflammation and its dysregulation during endotoxemia is a novel mechanism for LPS induced cardiovascular pathogenesis.

Extract from Bougainvillea xbuttiana (Variety Orange) Inhibits Production of LPS-Induced Inflammatory Mediators in Macrophages and Exerts a Protective Effect In Vivo

BioMed Research International ◽

10.1155/2019/2034247 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Rodolfo Abarca-Vargas ◽

Vera L. Petricevich

Keyword(s):

Inflammatory Mediators ◽

Ethanolic Extract ◽

Peritoneal Macrophages ◽

Experimental Models ◽

Nitric Oxide Release ◽

Lps Challenge ◽

Secretion Of Mediators ◽

Background. Different pharmacological properties, such as antioxidant, antiproliferative, and anti-inflammatory properties, have been described among natural products. We previously described that the Bougainvillea xbuttiana (Variety Orange) ethanolic extract (BxbO) has an anti-inflammatory effect; however, this action is not fully understood. In this study, the action of the BxbO extract on the secretion of inflammatory mediators in two experimental models, in vitro and in vivo, after LPS challenge was evaluated. Methods. Peritoneal macrophages were obtained from female BALB/c mice and LPS-challenged with or without the BxbO extract. For the evaluation of mediators, the supernatants at 0, 12, 24, 36, and 48 hours were collected. For in vivo estimation, groups of female BALB/c mice were first intraperitoneously injected with different amounts of LPS and later administered the oral BxbO extract (v.o.) for 144 hours. To understand the mechanism of action, sera obtained from mice were collected at 0, 2, 4, 8, 12, and 24 hours after LPS challenge (with or without BxbO) for the detection of mediators. Results. The results showed that, in both peritoneal macrophages and sera of mice treated with the BxbO extract 1 hour before or together with LPS challenge, proinflammatory cytokines and nitric oxide release were unquestionably repressed. In contrast, in both systems studied here, the IL-10 levels were elevated to 5 to 9 times. At lethal doses of LPS, the BxbO extract treatment was found to protect animals from death. Conclusions. The results revealed that the inhibitory, protective, and benign effects of the BxbO extract were due to its capacity to balance the secretion of mediators.

Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00256.2016 ◽

2017 ◽

Vol 312 (6) ◽

pp. G550-G558 ◽

Cited By ~ 44

Author(s):

Joseph B. J. Ward ◽

Natalia K. Lajczak ◽

Orlaith B. Kelly ◽

Aoife M. O’Dwyer ◽

Ashwini K. Giddam ◽

...

Keyword(s):

Bile Acid ◽

Ursodeoxycholic Acid ◽

Inflammatory Responses ◽

Lithocholic Acid ◽

Primary Metabolite ◽

Secondary Bile Acid ◽

Colonic Inflammation ◽

Inflammatory bowel diseases (IBD) comprise a group of common and debilitating chronic intestinal disorders for which currently available therapies are often unsatisfactory. The naturally occurring secondary bile acid, ursodeoxycholic acid (UDCA), has well-established anti-inflammatory and cytoprotective actions and may therefore be effective in treating IBD. We aimed to investigate regulation of colonic inflammatory responses by UDCA and to determine the potential impact of bacterial metabolism on its therapeutic actions. The anti-inflammatory efficacy of UDCA, a nonmetabolizable analog, 6α-methyl-UDCA (6-MUDCA), and its primary colonic metabolite lithocholic acid (LCA) was assessed in the murine dextran sodium sulfate (DSS) model of mucosal injury. The effects of bile acids on cytokine (TNF-α, IL-6, Il-1β, and IFN-γ) release from cultured colonic epithelial cells and mouse colonic tissue in vivo were investigated. Luminal bile acids were measured by gas chromatography-mass spectrometry. UDCA attenuated release of proinflammatory cytokines from colonic epithelial cells in vitro and was protective against the development of colonic inflammation in vivo. In contrast, although 6-MUDCA mimicked the effects of UDCA on epithelial cytokine release in vitro, it was ineffective in preventing inflammation in the DSS model. In UDCA-treated mice, LCA became the most common colonic bile acid. Finally, LCA treatment more potently inhibited epithelial cytokine release and protected against DSS-induced mucosal inflammation than did UDCA. These studies identify a new role for the primary metabolite of UDCA, LCA, in preventing colonic inflammation and suggest that microbial metabolism of UDCA is necessary for the full expression of its protective actions. NEW & NOTEWORTHY On the basis of its cytoprotective and anti-inflammatory actions, the secondary bile acid ursodeoxycholic acid (UDCA) has well-established uses in both traditional and Western medicine. We identify a new role for the primary metabolite of UDCA, lithocholic acid, as a potent inhibitor of intestinal inflammatory responses, and we present data to suggest that microbial metabolism of UDCA is necessary for the full expression of its protective effects against colonic inflammation.

Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2016-209424 ◽

2016 ◽

Vol 76 (3) ◽

pp. 612-619 ◽

Cited By ~ 37

Author(s):

E A Ross ◽

A J Naylor ◽

J D O'Neil ◽

T Crowley ◽

M L Ridley ◽

...

Keyword(s):

Inflammatory Arthritis ◽

Inflammatory Responses ◽

Vascular Endothelial Cells ◽

Bone Erosion ◽

Negative Regulator ◽

Mitogen Activated Protein Kinase ◽

Critical Determinant ◽

ObjectivesTristetraprolin (TTP), a negative regulator of many pro-inflammatory genes, is strongly expressed in rheumatoid synovial cells. The mitogen-activated protein kinase (MAPK) p38 pathway mediates the inactivation of TTP via phosphorylation of two serine residues. We wished to test the hypothesis that these phosphorylations contribute to the development of inflammatory arthritis, and that, conversely, joint inflammation may be inhibited by promoting the dephosphorylation and activation of TTP.MethodsThe expression of TTP and its relationship with MAPK p38 activity were examined in non-inflamed and rheumatoid arthritis (RA) synovial tissue. Experimental arthritis was induced in a genetically modified mouse strain, in which endogenous TTP cannot be phosphorylated and inactivated. In vitro and in vivo experiments were performed to test anti-inflammatory effects of compounds that activate the protein phosphatase 2A (PP2A) and promote dephosphorylation of TTP.ResultsTTP expression was significantly higher in RA than non-inflamed synovium, detected in macrophages, vascular endothelial cells and some fibroblasts and co-localised with MAPK p38 activation. Substitution of TTP phosphorylation sites conferred dramatic protection against inflammatory arthritis in mice. Two distinct PP2A agonists also reduced inflammation and prevented bone erosion. In vitro anti-inflammatory effects of PP2A agonism were mediated by TTP activation.ConclusionsThe phosphorylation state of TTP is a critical determinant of inflammatory responses, and a tractable target for novel anti-inflammatory treatments.