There are many research on anti-inflammatory drugs hence there is a requirement to understand the inflammatory process in order to understand the role of anti-inflammatory as well as immunosuppressive agents. Inflammation occurs in response to a pathogen (infection) and is a protective process to remove the harmful stimuli, thus promoting healing. Inflammation can also be induced by endoplasmic reticulum (ER) stress. There is acute inflammation like anaphylactic shock, which is short-term where reaction ceases when stimuli is removed, as well as chronic inflammation like asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis or artherosclerosis (1)(1,2), which are long-term. Acute inflammation is further divided into innate and adaptive response. There are different ways to detect inflammation in an individual, either physically or chemically. Five cardinal signs of an acute inflammation are pain, redness, immobility, swelling and heat. Interleukin-6 (IL-6) and lipopolysaccharide binding protein (LBP) are biomarkers that detect patient who are of septic risk in inflammatory processes.  Septic shock is an LPS-induced TLR4 response. (3)
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There are many pathways involved in inflammation. The NF-ÎºB pathway is one of the most important activators of pro-inflammatory cytokines and innate and chronic inflammatory processes(4) with iNOS and subsequent nitric oxide (NO) production and prostaglandin (PG) synthetase i.e. cyclooxygenase (COX) especially COX-2, being inflammatory mediators in response to the activated NF-ÎºB. PG inhibits NF-ÎºB activation?(4) 2 pathways of NF-ÎºB activation -> IKK activation -> initiate phosphorylation of IÎºB. Therefore inhibition or modulation of this pathway may prevent inflammation.(4)
Toll-like receptors (TLRs) are key molecules found on tissue macrophages (Rang&Dale) that triggers the body's immune response in the presence of microbial infection by recognising specific pathogen-associated molecular patterns (PAMPs) on each microorganism. (2,3) These PAMPs have respective TLRs of which 10 of them are known (2,3). For instance, peptidoglycan ligates with TLR2, synthetic double-stranded RNA (dsRNA) e.g. Poly I:C to TLR3, lipopolysaccharide (LPS) to TLR4 and CpG DNA motifs associated with bacterial DNA to TLR9. (3)
(Ligation of TLR4 to LPS is assisted by MD2, a polypeptide needed for LPS responsiveness. (Book) MD2 binds the outer region of TLR4 to enable TLR4 to bind to the inner lipophilic region of LPS. (Book) LPS on the other hand, is present in small amounts and sometimes requires CD14, a membrane protein found on monocytes, tissue macrophages and neutrophils, where LPS is extracted with the help of a lipopolysaccharide binding protein (LBP) through the exchange of lipids and mounted on the CD14 which functions as a mediator to present the LPS to the TLR4-MD2 complex in order to be recognised effectively. (Book)
The signal transduction pathways between each TLR are different. (3) However most of them interact with the adaptor protein myeloid differentiation primary response protein (88) (MyD88) which has two domains: the Toll/Interleukin-1 receptor (TIR) domain and the death domain. (3) After TLR-PAMP ligation, MyD88 is recruited to the TLR via a TIR to TIR interaction. (3) Then its death domain binds the death domain of an interleukin receptor-associated kinase (IRAK), causing its phosphorylation and dissociation from the receptor complex, consequently binding and propagating the signal to TNF-receptor-associated factor (TRAF) 6, a specific member of the TRAF family of adaptor proteins. (3,4) This pathway eventually activates the nuclear factor kappa B (NF-ÎºB) and mitogen-activated protein kinase (MAPK) pathway and the transcription of immunologically-relevant genes (3) TLR3 and TLR4 pathways are also found to induce NF-ÎºB and MAPK without MyD88, with delayed kinetics. (3)
Another adaptor molecule, TIR-associated protein (TIRAP, or also known as Mal) also propagate signals downstream of TLR1, TLR2, TLR4 and TLR6 (e.g. NF-ÎºB, MAPK and cytokine production) (3)
TLR4, but not TLR 2,5,6 could induce IRF3, a transcription factor essential for production of IFN-Î² and antiviral response. This is because there's another â€¦. (TRIF, also known as TIR-containing adaptor molecule [TICAM-1])) (3)
TLRs also determine the maturation of dendritic cells (DC), where DCs function as important antigen presenting cells (APC). Upon maturation, DCs secrete cytokines (e.g.IL-6, which relieves suppression of effector T cells by Treg (CD4+ CD25+) cells that suppress activity of self-reactive T cells in the periphery), present peptides to T cells and express co-stimulatory molecules on surface to give T cells the second signal (which is? To further stimulateâ€¦?). (3) However, since DC maturation depends on TLR ligation with PAMPs hence this adaptive response only occurs when infection is present i.e. when TLR stimulates DC maturation. (3)
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IRF3 pathway and DC maturation markers are independent of NF-ÎºB and MAPK, indicating that the MyD88-independent pathway did not involve TIRAP. (3)
In summary, TLR on macrophage interacts with PAMP on microorganism to trigger dendritic cell/macrophage to respond immediately, activating intracellular signal pathways. Subsequent reactions are production of main pro-inflammatory cytokines like TNF-Î± and IL-1 which causes expression of adhesion molecules on intimal surface or, other mediators like PGs and histamine (H2) that act on vascular endothelial cells of postcapillary venules, causing an increase in vascular permeability. (Rang&Dale)
There are now on-going treatments of inflammatory conditions with plants. (4) It is found (5) that a diet rich in polyphenolic compounds can improve health as well as decrease cardiovascular risks. Flavonoids are of this class of compounds and are low molecular weight plant metabolites largely found in some vegetables, fruits, seeds and beverages. (5) They exert anti-oxidant, anticancer, anti-allergic and anti-inflammatory effects. (5) ''Quercetin is a common dietary flavonoid component which inhibits production of the cytokine, tumour necrosis factor alpha (TNF-Î±), and gene expression in a dose-dependent manner in peripheral blood mononuclear cells (PBMC) via a modulation of NF-ÎºB1 and IÎºB.'' (5)
The aim of this research is to assess plant-derived natural products and synthetic small molecules as potential anti-inflammatory agents.
Explain adaptive response
1. Berberine inhibits HIV Protease Inhibitor-induced inflammatory response.pdf.
2. Hoffjan S, Stemmler S, Parwez Q, Petrasch-Parwez E, Arinir U, Rohde G, et al. Evaluation of the toll-like receptor 6 Ser249Pro polymorphism in patients with asthma, atopic dermatitis and chronic obstructive pulmonary disease. BMC Medical Genetics. 2005;6(1):34.
3. Kopp E, Medzhitov R. Recognition of microbial infection by Toll-like receptors. Current Opinion in Immunology. 2003 Aug;15(4):396-401.
4. Natural products as targeted modulators of the NFKB pathway edit.pdf.
5. Nair MP, Mahajan S, Reynolds JL, Aalinkeel R, Nair H, Schwartz SA, et al. The Flavonoid Quercetin Inhibits Proinflammatory Cytokine (Tumor Necrosis Factor Alpha) Gene Expression in Normal Peripheral Blood Mononuclear Cells via Modulation of the NF-ÎºÎ² System. Clin Vaccine Immunol. 2006 Mar;13(3):319-328.