Current and Future molecular mechanism in Inflammation and Arthritis

Abstract

Inflammation is an immune response of the human body but excessive inflammation is taken as a major factor in the development of many diseases including autoimmune disorders, cancer and nerve disorders etc. In this regards the need is to suppress the inflammatory response. Suppression of extra or imperfect inflammatory response is not a big deal provided there is an exact knowledge of particular target in the body. Recent advancements in Pharmacological aspect made the therapy with improved outcomes in number of patients. Anticytokine therapy might be one of the important and novel approaches for inflammation and Arthritis. This can be achieved only when we go through the pathophysiology of expression and identification of mediators. Let's take an example of cytokine like interleukins (IL), chemokines, interferons (INF), tumor necrosis factors (TNF-α), growth factors, and colony stimulating factors) release pathway which is a major signalling protein in inflammatory response. In the present study we have reviewed the recent pharmacological therapeutic advancement, inflammatory mediators, receptors, and major signalling pathways. Such information will not only provide the idea about the mechanism of action of Pharmaceuticals and molecular targets but also it provides a new aspect for drug designing and new corrective approaches in existing clinical medicines. This study will be a source of good information for the researchers working in the area of drug designing and molecular Pharmacology especially in anti-inflammatory and anti arthritic medicines for target based therapy.

Keywords: arthritis; cytokines; inflammation; receptors; transcription factor.

Figure 1

Nuclear Factor-κB pathway. The nuclear factor-kappa (NF-_B) level differently regulates cartilage homeostasis. Upon ligand binding to the receptor present on the cell surface, the activated IKK causes phosphorylation of IκB which further results in NF-κB activation which translocate to the nucleus where serves as a transcription factor and bind to DNA to induce NF-κB target gene transcription which further results in various cellular responses like Apoptosis, Inflammation, Proliferation and Hypertrophy in chondrocytes. NF- κB induces catabolic gene expression through NF-_B response elements located in the promoters of the MMP1, MMP9, MMP13 and ADAMTS5 genes.

Figure 2

Mitogen-Activated Protein Kinase (MAPK) cascade. This pathway plays a crucial role n the progression of Rheumatoid arthritis. MAPK pathway (right) are activated by the pro-inflammatory cytokines TNF-α and IL-1. MAPK cascade initiated by binding of ligands such as growth factors mitogens, cytokines and stress signals. MAPK cascade after phosphorylation of its components serves as transcription factor and binds to the DNA for genes coding for various cytokines including TNF-α and IL-1, other inflammatory molecules, such as prostaglandins (PGs), and proteases, such as the matrix metalloproteinases (MMPs). ERK1/2 controls PGE2 and MMP-1 production which contributes to the inflammation, angiogenesis, recruitment of cells from both innate and adaptive arms of the immune system, cartilage damage and bone erosion.

Figure 3

JAK-STAT signaling pathway. In mammals, the JAK/STAT pathway is the principal signaling mechanism for a wide array of cytokines and growth factors. Upon ligand binding, Jak associated with cytokine receptors undergo transphosphorylation and mediate phosphorylation of specific tyrosine residues on the cytokine receptor. Binding of cytokines to the receptors induces dimerization of these receptors and causes the phosphorylation of JAKs and STATs. Activation of STAT causes dimerization. These dimers serve as a transcription factor and causes transcription of Matrix Metallopeptidase 13(MMP-13). The JAK/STAT signal transduction pathway is utilized by many cytokines and growth factors that regulate gene expression and cellular activation, proliferation, and differentiation.

Figure 4

Arachidonic Acid Pathway. This Pathway involves the release of inflammatory mediators as Prostaglandins, thromboxanes, and leukotrienes as depicted in the figure. Phospholipase A2 activation initiates this pathway results in formation of Arachidonic Acid from the cell membrane. Then Arachidonic acid is metabolized into different mediators by some enzymatic reactions in presence of cyclooxygenase enzyme (COX) and Lipoxygenase (LOX).