S1654 Pro-Inflammatory Cytokines Regulate IL-1 Receptor 1(IL-1R1)/IL-1 Receptor Accessory Protein (IL-1racp) Signaling Through p38 MAPK to Decrease Gastric Barrier Function in Helicobacter pylori Infection

Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. This study aimed to identify potential natural product-derived inhibitory molecules against the p38α MAPK receptor to mitigate the eliciting of pro-inflammatory cytokines using computational techniques. The 3D X-ray structure of the receptor with PDB ID 3ZS5 was energy minimized using GROMACS and used for molecular docking via AutoDock Vina. The molecular docking was validated with an acceptable area under the curve (AUC) of 0.704, which was computed from the receiver operating characteristic (ROC) curve. A compendium of 38,271 natural products originating from Africa and China together with eleven known p38 MAPK inhibitors were screened against the receptor. Four potential lead compounds ZINC1691180, ZINC5519433, ZINC4520996 and ZINC5733756 were identified. The compounds formed strong intermolecular bonds with critical residues Val38, Ala51, Lys53, Thr106, Leu108, Met109 and Phe169. Additionally, they exhibited appreciably low binding energies which were corroborated via molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The compounds were also predicted to have plausible pharmacological profiles with insignificant toxicity. The molecules were also predicted to be anti-inflammatory, kinase inhibitors, antiviral, platelet aggregation inhibitors, and immunosuppressive, with probable activity (Pa) greater than probable inactivity (Pi). ZINC5733756 is structurally similar to estradiol with a Tanimoto coefficient value of 0.73, which exhibits anti-inflammatory activity by targeting the activation of Nrf2. Similarly, ZINC1691180 has been reported to elicit anti-inflammatory activity in vitro. The compounds may serve as scaffolds for the design of potential biotherapeutic molecules against the cytokine storm associated with COVID-19.

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Role of p38 MAPK and pro‐inflammatory cytokines expression in glutamate‐induced neuronal death of neonatal rats

International Journal of Developmental Neuroscience ◽

10.1016/j.ijdevneu.2008.02.008 ◽

2008 ◽

Vol 26 (5) ◽

pp. 487-495 ◽

Cited By ~ 23

Author(s):

V. Chaparro‐Huerta ◽

M.E. Flores‐Soto ◽

G. Gudiño‐Cabrera ◽

M.C. Rivera‐Cervantes ◽

O.K. Bitzer‐Quintero ◽

...

Keyword(s):

P38 Mapk ◽

Inflammatory Cytokines ◽

Neuronal Death ◽

Neonatal Rats ◽

Pro Inflammatory Cytokines

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Glyoxal and Methylglyoxal as E-cigarette Vapor Ingredients-Induced Pro-Inflammatory Cytokine and Mucins Expression in Human Nasal Epithelial Cells

American Journal of Rhinology and Allergy ◽

10.1177/1945892420946968 ◽

2020 ◽

pp. 194589242094696

Author(s):

Soyoung Kwak ◽

Yoon Seok Choi ◽

Hyung Gyun Na ◽

Chang Hoon Bae ◽

Si-Youn Song ◽

...

Keyword(s):

Epithelial Cells ◽

Signaling Pathway ◽

P38 Mapk ◽

Inflammatory Cytokines ◽

Water Soluble ◽

Nasal Epithelial Cells ◽

Airway Diseases ◽

Human Nasal Epithelial Cells ◽

Specific Inhibitors ◽

Pro Inflammatory Cytokines

Background Glyoxal (GO), and methylglyoxal (MGO) are among the most toxic compounds emitted by electronic cigarette (E-cig) and regular tobacco cigarette smoke. Airway diseases presented mucus over production as their major pathophysiologic feature. However, the effects of GO and MGO on pro-inflammatory cytokines and mucin expression in human nasal epithelial cells, as well as the underlying signaling pathway, have not yet been studied. Objective This study is to determine whether GO and MGO induce pro-inflammatory cytokines, and MUC5AC/5B expression via mitogen-activated protein kinase (MAPK)s and nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways. Methods The effect of GO, and MGO on pro-inflammatory cytokines, mucins expression and the signalling pathway of GO and MGO were investigated using water-soluble tetrazolium salt-1, enzyme immunoassays, and immunoblot analysis with specific inhibitors and small interfering RNA. Results GO and MGO did not affect cell viability up to 2 mM in human nasal epithelial cells. GO and MGO increased production of pro-inflammatory such as interleukin (IL)-1β and IL-6) and MUC5AC/5B. Additionally, GO and MGO significantly activated extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK, and NF-κB. Whether ERK1/2, p38 MAPK, and NF-κB signaling pathway were involved in GO and MGO-induced production of pro-inflammatory cytokines (IL-1β and IL-6) and MUC5AC/5B, we used specific inhibitors and siRNA transfection. These significantly repressed GO- and MGO-induced expression of pro-inflammatory cytokines (IL-1β and IL-6) and MUC5AC/5B. Conclusions GO and MGO induced pro-inflammatory cytokines and MUC5AC/5B expression via ERK1/2, p38 MAPK, and NF-κB in human nasal epithelial cells. These results suggested that GO and MGO may be involved in mucus hypersecretion-related airway diseases.

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Double gastric infection with Helicobacter pylori and non-Helicobacter pylori bacteria during acid-suppressive therapy: increase of pro-inflammatory cytokines and development of atrophic gastritis

Alimentary Pharmacology & Therapeutics ◽

10.1046/j.1365-2036.2001.01029.x ◽

2001 ◽

Vol 15 (8) ◽

pp. 1163-1175 ◽

Cited By ~ 58

Author(s):

S. Sanduleanu ◽

D. Jonkers ◽

A. De Bruïne ◽

W. Hameeteman ◽

R. W. Stockbrügger

Keyword(s):

Helicobacter Pylori ◽

Atrophic Gastritis ◽

Inflammatory Cytokines ◽

Suppressive Therapy ◽

Pro Inflammatory Cytokines

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miR‑148a inhibits pro‑inflammatory cytokines released by intervertebral disc cells by regulating the p38/MAPK pathway

Experimental and Therapeutic Medicine ◽

10.3892/etm.2018.6516 ◽

2018 ◽

Author(s):

Guangfeng Li ◽

Xianye Tang ◽

Hongliang Chen ◽

Wei Sun ◽

Feng Yuan

Keyword(s):

Intervertebral Disc ◽

P38 Mapk ◽

Inflammatory Cytokines ◽

Mapk Pathway ◽

P38 Mapk Pathway ◽

Disc Cells ◽

Pro Inflammatory Cytokines

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The Role of Toll-like receptor 4 in respiratory syncytial virus replication, interferon lambda 1 induction, and chemokine responses

10.1101/404384 ◽

2018 ◽

Author(s):

Lindsay Broadbent ◽

Jonathon D. Coey ◽

Michael D. Shields ◽

Ultan F. Power

Keyword(s):

Respiratory Syncytial Virus ◽

Immune Responses ◽

P38 Mapk ◽

Inflammatory Cytokines ◽

Virus Replication ◽

Growth Kinetics ◽

Rsv Infection ◽

Syncytial Virus ◽

Pro Inflammatory Cytokines

AbstractRespiratory syncytial virus (RSV) infection is the leading cause of severe lower respiratory tract infections (LRTI) in infants worldwide. The immune responses to RSV infection are implicated in RSV pathogenesis but RSV immunopathogenesis in humans remains poorly understood. We previously demonstrated that IFN-λ1 is the principle interferon induced following RSV infection of infants and well-differentiated primary pediatric bronchial epithelial cells (WD-PBECs). Interestingly, RSV F interacts with the TLR4/CD14/MD2 complex to initiate secretion of pro-inflammatory cytokines, while TLR4 stimulation with house dust mite induces IFN-λ1 production. However, the role of TLR4 in RSV infection and concomitant IFN-λ1 induction remains unclear. Using our RSV/WD-PBEC infection model, we found that CLI-095 inhibition of TLR4 resulted in significantly reduced viral growth kinetics, and secretion of IFN-λ1 and pro-inflammatory chemokines. To elucidate specific TLR4 signalling intermediates implicated in virus replication and innate immune responses we selected 4 inhibitors, including LY294002, U0126, SB203580 and JSH-23. SB203580, a p38 MAPK inhibitor, reduced both viral growth kinetics and IFN-λ1 secretion, while JSH-23, an NF-κB inhibitor, reduced IFN-λ1 secretion without affecting virus growth kinetics. Our data indicate that TLR4 plays a role in RSV entry and/or replication and IFN-λ1 induction following RSV infection is mediated, in part, by TLR4 signalling through NF- κB and/or p38 MAPK. Therefore, targeting TLR4 or downstream effector proteins could present novel treatment strategies against RSV.ImportanceThe role of TLR4 in RSV infection and IFN-λ1 induction is controversial. Using our WD-PBEC model, which replicates many hallmarks of RSV infection in vivo, we demonstrated that the TLR4 pathway is involved in both RSV infection and/or replication and the concomitant induction of IFN-λ1 and other pro-inflammatory cytokines. Increasing our understanding of the role of TLR4 in RSV immunopathogenesis may lead to the development of novel RSV therapeutics.

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