Inflammation is a biological response orchestrated by the immune system in response to harmful stimuli such as pathogens and tissue damage. However, in some circumstances the inflammatory response can become inappropriate and over stimulated and begin attacking the body's own tissues resulting in an inflammatory disease. It is not yet clear what causes the immune system to initiate such an unregulated inflammatory response. However, key players thought to initiate the process are cytokines and their soluble receptors.
In order treat inflammatory diseases, many studies have been investigated into inflammatory medicators. The investigations mainly have the aim of halting the effects of cytokine signalling through the use of monoclonal antibodies and pyrrolidinesulphonylaryl molecules such as Tocilizumab, infliximab and Compound 6a (Smolen et al, 2008); Zinzalla et al, 2010) or adapting the antagonistic properties of soluble cytokine receptors (sCR's).
Cytokines are a group of glycoproteins that act by binding to specific membrane bound receptors on target cells. This results in the activation of secondary messenger and signal transduction pathways within the cell (Smith and Humphries, 2009). Recent investigations suggest that In vivo, soluble cytokine receptors (sCR's) act as antagonists by either proteolytic cleavage of the membrane bound receptors or alternative mRNA Splicing resulting in the inhibition cytokine signalling. If this potential could be utilised it could be the key to preventing inflammatory disease and since sCR's are induced by their corresponding cytokine, their concentration may reflect cytokine activity.
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In contrast, in certain circumstances, sCR's can make an exception to this rule and act as agonists via a method called trans-signalling which involved the promotion cytokine signalling. There is considerable evidence suggesting that sCR's are the natural homeostatic regulators of the actions of cytokines. It is suggested that sCR levels, rather than cytokine levels, are more reliable markers of cytokine activity and, hence, of inflammatory activity. Therefore, the majority of current investigations are aimed at trying to discover if this hypothesis is true and if sCR's are able to be manipulated in order to control or even halt inflammatory disease.
The current cytokines of interest are the proinflammatory cytokines Interleukin 1b (IL-1b), tumour necrosis factor a (TNF-a), and Interleukin 6 and their sCRs sIL-6R, sgp130, sIL-1RI, sIL-1RII (Fig 1.0 (b), sTNFRI and sTNFRII. sgp130, sIL-1RI, sIL-1RII, sTNFRI and sTNFRII. In this review, the conflict of antagonistic and agonistic sCR's shall be discussed.
Role of Soluble cytoline receptors as antagonists and their role in inflammation.
Crohns disease (CD) is an inflammatory disease of the gut resulting from an inappropriate immune response to the gut lumen microflora. This is induced by bacterial recognition via toll like receptors expressed on epithelial cells and mucosal macrophages which initiates the release of proinflammatory mediators Interleukin 1b (IL-1b), tumour necrosis factor a (TNF-a), and IL-6. (Cario and Podolsky (2000) cited by Gustot (2010))
In a study by Gustot et al 2010, sCR's were examined in quiescent and active CD. sCR's sIL-6R, sgp130, sIL-1RI, sIL-1RII, sTNFRI and sTNFRII were examined. The study's results observed increased levels of sTNFRI, sTNFRII, sIL-1RI, IL-6, and sIL-6R in patients with active CD compared CD patients in clinical remission and Healthy subjects. Indicating agonsistic properties of these sCR's. However, sIL-1RII and sgp130 were significantly decreased in active CD indicating that these sCR's may hold antagonistic capabilities. When compared to ulcerative colitis (UC), an inflammatory disease of the large intestine it was concluded that reduced production of sIL-1RII was restricted to CD. The study demonstrated that Soluble IL-1RII could function as an inhibitor of the IL-1b pathway by capturing IL-1 and preventing its interaction with the sIL-1RI or by inhibiting the processing of the pro-IL-1b molecule and the formation of the active cytokine. (Gustot et al, 2010).
Decreases of sIL-1RII and sgp130 might be essential to the pathogenesis and course of CD but not in all inflammatory bowel disease as emphasised by the finding of deregulation of anti inflammatory sIL-1RII compared with UC.
Soluble TNFÎ± (sTNFÎ±) - Agonist ?
TNFÎ± is released mainly from monocytes and Lymphocytes in response to inflammatory stimuli and has been a keen sCR of interest for many inflammatory diseases such as Primary Billary cirrohsis, Alzehimers and Parkinsons disease (Shiraki et al, 2010; Scalzo et al, 2009).
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Two sCR's of interest are sTNF-RI, and sTNF-RII. These receptors act as inhibitors of TNF-Î± activity by blocking TNF-a activity by competing with cell-surface TNFR or prolonging the biological effect of TNF-Î± as a buffer system. Elevation of serum TNF-Î±, sTNF-RI, and sTNF-RII concentrations correlated with disease severity in cirrhotic patients (Naveau, S et al, 1998).
Therefore, proposing that sTNF receptors can stabilize and preserve circulating soluble TNFÎ± and thus function as TNFÎ± agonists (Shiraki et al, 2010).
Parkinsons disease (PD) is a chronic neurodegenerative disease characterized by a progressive and irreversible loss of the dopaminergic neurons of the substantia nigra pars compacta (Samii et al, 2004). It is characterised by resting tremor, bradykinesia, muscular rigidity. Inflammation is initiated by microglial release of proinflammatory cytokines which act on the endothelium of blood-brain barrier cells which in turn stimulate upregulation of adhesion molecules. The upregulation of adhesion molecules leads to the recruitment of passing T cells and monocytes, which express counter receptors that then release yet more proinflammatory cytokines (Reale et al, (2008). A study by Scalzo et al, 2009, demonstrated that patients with Parkinsons disease and healthy controls showed no significant difference in TNFÎ± levels but did show elevated circulating levels of sTNFI and sTNFII in PD patients. Implying, that sTNFR1 and sTNFR2 may be homeostatic regulators of TNF-Î± and therefore may be more reliable markers of inflammatory activity (Grassi-Oliveira et al., 2009).
However, in similair studies as that conducted by Brodacki et al. (2008) and Shiraki et al, (2010) serum TNFÎ± was elevated in patients with PD in comparision to healthy controls. The study by Scalzo et al, (2009) used 46 patients compared to by Brodacki et al. (2008) patient cohort of 75 patients and the mere 12 patients in the study by Shiraki et al, (2010). All studies current clinical scales such as Parkinson's Disease Rating Scales and Child-Pugh classification (Cirrhosis) to determine correct diagnosis of the inflammatory disease. The main difference was the test methodology where Brodacki et al. (2008) used Flow cytometry which does tend to hold a greater sensitivity and specificity in comparison to ELISA used by Scalzo et al, (2009) and Shiraki et al, (2010) . However, negating that their can be discrepancies caused by different methologies and therefore a comparison study perhaps using both methodologies may give clearer results (Leng, S et al, 2008).
sIL-6 - Agonist
IL-6 is considered to play a pivotal role in chronic inflammation and is found in excess at sites of inflammation. IL-6 levels are considerably elevated in the serum of Rheumatoid Arthritis (RA) patients and can be directly correlated to disease activity. In addition, high levels of soluble IL-6 receptor (sIL-6R) have been shown to correlate with the degree of joint destruction (Robak, T et al, 1996; Jazayeri et al, 2010). sIL-6R acts as an agonist for IL-6 activity and requires a membrane bound receptor complex (Fig 1.0 (a)), composed of a ligand binding Î±-chain IL-6R Î²-chain gp130R. However, instead of acting as a regulator of IL-6, sil-6 interacts with IL-6 to form an agonistic complex which signals via gp130, independently from membrane anchored IL-6R enhancing IL-6 in vivo by 10-100 fold and resulting in trans -signalling.
However, lung inflammation plays a pivotal role in the pathogenesis of airway disease such as cystic fibrosis (CF) (Delacourt C, 2003; McGreal, E, 2010). However, despite inflammation present in the lung and other elevated markers of inflammation such as IL-8 and MCP-1, IL-6, expression of sIL-6R and sgp130 in CF was no different to control patients. Degradation of sIL-6 by CF BALF purified serine proteases was also investigated which identified neutrophil derived serine protease activity as the major mediator of degradation of IL-6, sIL-6R and sgp130 in the CF lung (McGreal, E, 2010). Therefore, implying that not necessarily in all cases of inflammation does sIL-6 and IL-6 play such a pivotal role and perhaps other influences other than sCR's may be at work such as Receptor for Advanced Glycation Endproducts (RAGE). RAGE is a member of the immunoglobulin superfamily and acts as an ubiquitous receptor present on epithelial, neuronal, vascular and inflammatory cells. Ligand binding to full-length RAGE can result in cellular activation and receptor-dependent signaling leading to inflammation and cellular stress. It is usually expressed at low levels in homeostasis but increases expression at sites of stress or injury and particularily in the lung RAGE can reach relatively high basal levels of expression.
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Such a hypothesis was noted by Jazayeri et al, 2010, that the role of other members of the IL-6 cytokine subfamily such as leukemia inhibitory factor , oncostatin M, ciliary neurotrophic factor , IL-11, cardiotrophin like cytokine and cardiotrophin-1in the pathogenesis of inflammatory diseases such as CF and RA had not yet been fully investigated and further research is required.
Amongst soluble cytokine receptors, sIL-1RI, TNFRI and TNFRII and sIL-6 have been studied the most. Understandably from the substantial body of evidence implicating that sCR's are key players involved in inflammatory diseases. However, but they also appear to be involved in several other diseases, such as essential thrombocytosis (Goett et al, 2010) and depression. Other influences may also be involved in the course of the inflammatory response such as Receptor for Advanced Glycation End products (RAGE). Similar to other sCR's soluble RAGE (sRAGE) is also generated either by alternative splicing or by proteolysis and can act as an antagonist in order to reduce the severity of full length RAGE interactions. sRAGE achieves this by preventing ligands from binding to the full-length RAGE. This can inhibit the proinflammatory responses involved in inflammatory disease states and had been studied recently with regards to Alzheimer's disease (Lue et al, 2009) and Rheumatoid Arthritis (Chen et al, 2009).
In view of the ongoing need for alternative treatments inflammatory diseases which do not respond initially to the currently available biologic therapies and for those patients who either cannot tolerate these agents, it is important to evaluate the predictive capacity of sCR's as biomarkers of disease such as serum cytokine concentrations in order to forecast the likely response of emerging therapies such as to infliximab and Tocilizumab. These studies should include an assessment of the full array of proinflammatory sCR's and other ligand receptors, as well as more standardisation of methodologies in order to avoid conflicting evidence between investigations.
1. Gustot, T. et al, (2010) Profile of soluble cytokine receptors in Crohn's disease. GUT. 54:488-495.
The aim of this study was to examine the profile of sCRs in Crohn's Disease patients and their effectiveness when challenged with Infliximab and corticosteroids. Infliximab is a monoclonal antibody against the proinflammatory cytokine TNF-Î± and corticosteroids are known powerful anti-inflammatories. This study demonstrated the antagonistic and agonistic behaviour of soluble cytokine receptors in particular sIL-6R, sgp130, sIL-1RI, sIL-1RII, sTNFRI and sTNFRII. It demonstrated that antagonistic sCR's were decreased in active disease implicated that there must be a mechanism suppressing the expression of agonistic sCR's in this inflammatory disease. The study also tried to confirm these findings by comparing their results with another inflammatory bowel disease such as Ulcerative colitis. Interestingly, the findings in patients with ulcerative colitis were not comparable to the results found in patient with Crohn's disease, further verifying that other mechanisms must be at work.
2. Scalzo, P et al (2010). Increased serum levels of soluble tumour necrosis factor-Î± receptor-1 in patients with Parkinson's disease. Journal of Neuroimmunology 216. 122-125.
This study looked at TNF-Î± and its soluble cytokine receptors TNF-RI and TNF-RII. This study claimed to be the first to assess levels of sCR's TNF-Î± in Parkinson's disease and it aimed clarify the role and extent of TNF-Î± and it's soluble receptors in Parkinson disease due to a range of previous conflicting data from other papers such as those from Brodacki et al. (2008) and Shiraki et al, (2010). Compared to other studies and current hypothesis that there would be an increase in TNF-Î± and it's soluble receptors due to their proinflammatory effect. This study found no differences in TNF-Î± and sTNFR2 levels compared to healthy controls. However, what this study did demonstrate was that Parkinson's disease patients had higher circulating levels of TNF-RI and that this correlated with patients with late disease onset.
Although, this study didn't confirm the significance of sCR's it did draw attention to methodologies used in measuring sCR's such as sample size and validity of the sample cohort, such as taking into consideration the age of the patients and phenotype of the disease ensuring that these factors do not affect data interpretation.
3. McGreal, E. (2010) Inactivation of IL-6 and soluble IL-6 receptor by neutrophil derived serine proteases in cystic fibrosis. Biochimica et Biophysica Acta 1802, 649-658.
The aim of this study was to determine the levels of soluble IL-6 receptor (sIL-6R) in cystic fibrosis patients. Patients with cystic fibrosis suffer from poorly resolved neutrophillic inflammation of the lungs and despite this IL-6 a key cytokine of inflammation has previously been measure at low levels. As described in previous studies such as those by Gustot, T. et al, (2010) sCR's to IL-6 may be better markers of inflammatory activity.
Bronchoalveolar lavage fluid (BALF) from 28 paediatric CF patients was taken and as expected the infiltrate was dominated by neutrophils. Other markers of inflammation such as IL-8 and MCP-1 were elevated but IL-6 although present was not found to be significantly elevated compared to healthy controls. It was also found that expression of sIL-6R and sgp130 was also low but this could be down to the process of sampling itself or caused by degradation from purified serine proteases (elastase, cathepsin G and proteinase 3) which would result in a loss of trans-signalling activity. This study observed an effect contrary to previous studies that neither IL-6 nor its soluble receptor was key into the development of inflammation.
4. Chen, Y et al (2009). Serum levels of soluble receptor for advanced glycation end products and of S100 proteins are associated with inflammatory, autoantibody, and classical risk markers of joint and vascular damage in rheumatoid arthritis. Arthritis Research & Therapy 2009, 11: 1-11.
The study by Chen et al, 2009, identifies another source of soluble receptor other than sCR that could cause an agonistic (Full length RAGE) and antagonistic (sRAGE) effect on the inflammatory response. Multi-ligand receptor for advanced glycation end products (RAGE) have been identified in numerous inflammatory diseases and appears to be an area of great interest alongside soluble cytokine receptors. Experimental evidence using pharmacological antagonists of RAGE and genetically modified mice suggests that blocking Full length RAGE halts progression of the inflammatory response. In animal models, administration of soluble RAGE, suppresses immediate and chronic inflammatory responses. (Yan, S et al. 2003). Due to the substantial body of evidence building about RAGE's effects in inflammatory disease there is still a great deal f research to be done towards investigating the mechanisms of RAGE and sCR's together in order to build a better understanding of what needs to be achieved in order or to control or prevent inflammatory disease.