Chemokines inflammatory diseases

Inhibition of inflammatory cytokines (Fig. 2) Humanized monoclonal anti-TNF antibodies (Infliximab (Remicade ), Adalimumab (Humira )) bind with high selectivity to human TNF-a and neutralize its activity. Thereby, infliximab decreases the effects of enhanced TNF levels during inflammatory disease such as production of proteases, chemokines, adhesion molecules, cyclooxygenase products (prostaglandins), and proinflammatory molecules such as interleukin-1 and -6. The antibodies may also recognize membrane-bound TNF-a on lymphocytes and other immune cells. These cells may subsequently become apoptotic or are eliminated via Fc-receptor-mediated phagocytosis. 

It is well established that NF-kB signaling plays a critical role in inflammation and immunity. Understanding the mechanism of NF-kB involvement in opioid receptor activation and chemokine expression may provide a vital key to understanding this complex signaling network. However, the elucidation of molecular mechanisms following activation of the opioid receptor family could aid in the development of future therapeutics for immune system-related and inflammatory diseases, drug addiction and HIV infection. 

CXCR2 is a member of the CXC family of chemokine receptors. IL-8 activates this receptor, and an antagonist would potentially be useful for the treatment of inflammatory diseases. Baxter et al. [58] describe the parallel optimization of binding and functional potency, physicochemical properties, ADME properties, and PK. The thiol of the HTS hit was varied with typical replacements (i.e., OH, NH2, SMe, NHAc, etc.), but this only led to inactive compounds. Variation of the substituent at N(2) showed that a benzyl moiety was required (Ph, Me substituents gave inactive compounds). Variation of the C(5) substituent showed that -substituents produced optimal activity. The optimized lead has substantially improved CXCR2 binding and functional activity as well as an excellent PK profile (Scheme 13). 

It seems obvious to assume that by virtue of their powerful regulatory effects of leukocyte recruitment, many chemokine/chemokine receptors may play an important role in an inflammatory disease of the joints such as RA. However, chemokines may have other effects in disease pathogenesis that may not be related to leukocyte chemotaxis. 

Haringman JJ, Kraan MC, Smeets TJ, Zwinderman KH, Tak PP. Chemokine blockade and chronic inflammatory disease proof of concept in patients with rheumatoid arthritis. Ann Rheum Dis 2003 62(8) 715-721. 

During chronic inflammatory disease, inflammatory cells (neutrophils, mast cells, macrophages, and lymphocytes) become increasingly more damaging to tissues. Anti-inflammatory action of Bik reduces cell death mediated by immune cell. Proinflammatory cytokine tumor necrosis factor-a (TNF-q) and interleukin-1 (3 (IL-1) cause expression of multiple inflammatory and innate immunity genes for additional cytokines, chemokines, adhesion molecules, and enzymes. Aprotinin has been reported to cause a reduction in apoptosis in vivo by decreasing inflammatory cytokine expression (IL-1, IL-6, and TNF -a) thus preventing caspase-8 activation [81],... 

Blocking of chemokine receptors by modifying their corresponding ligands is a promising therapeutic strategy in inflammatory diseases and HIV infection. With the method described here, chemokine derivatives can easily be expressed in a short time and in sufficient amounts. 

The availability of large amounts of raw sequence data, due to public EST collections, and the ability of scientists to access this data, has led to a massive increase in the number of novel proteins identified in silico—that is purely on computational techniques. Nowhere has this been as fruitful as in the chemokine area where there has been an explosive increase in the number of chemokines identified. The challenge now is to piece together the roles that these new chemokines play in routine immunosurveillance and also in inflammatory diseases. This challenge has been taken up in the last year with the identification of ligands for four chemokine receptors previously classified as orphans. In terms of receptor function, we still have a long way to go, since there are still many chemokines for which receptors have not been identified, but at least we have a more complete list of the players as far as the ligands are concerned. 

Chemokine accumulation occurs in autoimmune degenerative disease such as multiple sclerosis and in allergic inflammatory diseases such as asthma. Various viruses produce CH antagonists that interfere with the CH-mediated defence system and HIV-1 infects cells via the CCR5 receptor. 

Inhibitors of chemokine receptors are not only potential therapeutics against inflammatory diseases, but also cancer therapeutics. Recently, several studies reported that many cancer cell lines possess a high metastatic index via chemokine-mediated migration [20,21]. 

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