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Saudi Journal of Kidney Diseases and Transplantation
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REVIEW ARTICLE Table of Contents   
Year : 2004  |  Volume : 15  |  Issue : 4  |  Page : 473-485
Cytokines and Glomerulonephritis


Kanoo Kidney Centre, Dammam Central Hospital, Dammam, Saudi Arabia

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How to cite this article:
Karkar A. Cytokines and Glomerulonephritis. Saudi J Kidney Dis Transpl 2004;15:473-85

How to cite this URL:
Karkar A. Cytokines and Glomerulonephritis. Saudi J Kidney Dis Transpl [serial online] 2004 [cited 2019 Oct 19];15:473-85. Available from: http://www.sjkdt.org/text.asp?2004/15/4/473/32880

   Introduction Top


Inflammation is the local and systemic res­ponse of the body to different immunological and non-immunological stimuli that enable it to defend itself and repair tissue damage. Inflammation can be initiated by an immune reaction such as formation of antibody-antigen immune complexes, e.g. anti-glomerular base­ment membrane disease, or by sensitized T­cells as in the delayed type hypersensitivity reaction. Glomerulonephritis can occur either as an isolated local acute inflammatory reaction or as part of a systemic inflammatory disorder as in systemic vasculitis. Inflammation can also be initiated by trauma, tissue necrosis or infection. [1]

The severity of injury in glomerulonephritis was traditionally thought to be directly related to the amount of immune reactants deposited in the kidney; e.g. deposition and fixation of antibodies to glomerular basement membrane (GBM) with complement fixation and binding of leucocytes to the Fc receptors; injury itself was caused by leucocytes infiltrating the kidney. [2] More recently, this process has been shown to be much more dynamic and the severity of injury caused by deposition of a defined amount of antibody could be radically altered, e.g. the presence of inter­current infection or the exposure to components of bacterial products such as lipopolysaccharide (LPS). In fact, intercurrent bacterial infection exacerbates immunologically mediated injury in a variety of situations. These include many types of glomerulonephritis, such as mesangial IgA disease, [3] mesangiocapillary glomerulo­nephritis, [4] Goodpasture's syndrome, [5] systemic lupus erythematosus [6] and systemic vasculitis. 7 In some instances, such relapses appear to be related to changes in the inflammatory response rather than to the underlying immuno­pathology; e.g. the infection associated relapse in patients with anti-GBM disease occurs without change in the serum concentration of the anti-GBM antibodies. [5] It is now apparent that the interaction between leucocytes and endothelium, the first step in an inflammatory response, is influenced by the cytokines that alter the effectiveness of this interaction and the capacity of leucocytes to release these inflammatory mediators.


   Background Top


Macrophages have long been known to release substances with potential effects on the severity of inflammation. Initially, they were defined by "activities"; in other words by the effects of macrophages on particular functional assays. Such assays were used to demonstrate a wide variety of factors, e.g. "macrophages activating factor", "leucocyte endogenous pyrogen" and "leucocyte migration inhibition factor". 8 Developments in molecular biology have resulted in the genes for an increasing number of these factors (cytokines) being cloned and expressed to produce recom­binant molecules; these include tumour necrosis factor (TNF), interferons, many types of inter­leukins (e.g. IL-1), chemokines, and various types of growth factors. These factors or cytokines were initially called lymphokines or monokines according to the source. Then they were referred to as interleukins when found to be released by leucocytes and modulating their functions. [9] Now, because they are known to be synthesized by and act on many cell types, they are referred to as cytokines.


   Definition Top


Cytokines are small molecular weight glycol­proteins range from 8-30 Kilo Dalton (KDa). They are produced by monocytes/macrophages and by other cell types including lymphocytes, neutrophils and glomerular mesangial, endo­thelial and epithelial cells. They are usually produced transiently and have short half lives. They are very potent and act in picomolar concentrations; hence they are produced in small amounts.

Cytokines have multiple overlapping fun­ctions. They are local inflammatory mediators rather than hormones and perform their functions mainly in an autocrine and paracrine fashion. Some cytokines have pro-inflamma­tory, while others have anti-inflammatory effects. Their main functions are to stimulate the immune cell growth and differentiation 10 and to induce and downregulate different sets of cytokines, leading to tissue repair and remodelling. [11],[12]

Chemokines are a group of 8-10 KDa cyto­kines that comprise structurally related proteins, which play a vital role during inflammatory and immunological responses [13],[14] The chemokines exhibit chemotactic activity towards specific target cells and promote various pro-inflam­matory events. They include IL-8, macrophage inflammatory protein-2 (MIP-2), platelet factor 4 (PF4), thromboglobulin and interferon­inducible protein-10 (IP-10), which most are specific for neutrophils. MIP-2 appears to be particularly important in rats as they do not express IL-8. [15],[16] Other chemokines include Rantes (regulated on activation, normal T expressed and secreted), macrophage chemo­tactic protein-1 (MCP-1) and MlP-lα and MIP-1β . [17],[18],[19] Growth factors are another group of cytokines that are responsible for cell growth and differentiation. These include transforming growth factor (TGF), platelet derived growth factor (PDGF), basic fibroblast growth factor (b-FGF), insulin-like growth factor (ILGF) and vascular endothelial growth factor (VEGF). Many of them, however, also cause potent immunosuppressive effect or activation of the immune system. TGF-β , for instance, they has the capacity to stimulate the growth and differentiation of suppressor T-cells and increase the synthesis of the natural inhibitors, i.e. soluble cytokines receptors and interleukin-1 receptor antagonist (IL-lra). PDGF, on the other hand, plays an important role in the migration of the progenitor cells into the glomerulus, whereas bFGF has been linked to the proli­feration of repopulating mesangial cells within glomeruli. [20]

In the past 20 years, research has lead to cloning and expression of a large number of cytokines, which have become increasingly relevant to many different areas of the bio­logical sciences and medicine, and in particular to the field of renal inflammation. Growth factors have also been shown to play an important role in the remodelling and scarring of glomerular and tubular cells. For instance, TGF-β has the capacity to increase the synthesis of extracellular matrix within glomeruli, whereas PDGF is well known to cause mesan­gial cell proliferation and mesangial expansion.

This review will focus mainly on those cytokines that have been shown in different in vitro and in vivo studies to play a pivotal role in glomerulonephritis.

Pro-inflammatory Cytokines

Endotoxins are known to be the pathogenetic factor of gram-negative bacteria. Shear and his colleagues in early 1940s isolated the active agent of endotoxin (bacterial lipopoly­saccharide, LPS); a component of the cell walls of certain bacteria from cultures of Serratia organisms. Endotoxin or LPS consists of lipid-A, a core polysaccharide and the O­specific antigen; the biological activity is known to reside in lipid-A. [21] Many of the deleterious consequences of infection can be reproduced in animal models [22] as well as in human beings [23] by injecting endotoxins. Systemic administration of LPS has profound biological effects in vivo and is the principal cause of endotoxic shock associated with gram negative sepsis. Many of the effects of LPS are mediated by cytokines like TNF and IL-1.

Tumor necrosis factor and IL-1 are two cytokines that share many pro-inflammatory properties [24] and act synergistically. [25 ] TNF is a 17.5 KDa polypeptide, which circulates as a trimer and is present in two forms; TNF-α and TNF-β . TNF-0 or cytotoxin was first identified by Carswell et al. in 1975 [26] in the sera of mice infected with Bacille Calmette-Guerin (BCG) and subsequently treated with endotoxin. They found that it caused hemorrhagic necrosis of selective tumors when injected systemically into mice. TNF-α has also been termed 'Cachectin' due to its role in the induction of a wasted or cachectic state through its effective inhibition of the enzyme lipoprotein lipase, resulting in lipemia and mainly hypertriglyceridemia. [27] TNF-β or lymphotoxin has been isolated from the culture fluid supernatant of antigen or mitogen stimulated peripheral blood leuco­cytes. [28] TNF-α and TNF-β exhibit similar and widely overlapping biological activities with respect to inflammation and anti-tumor effect both in vitro and in vivo. [27] Their genes are adjacent to each other and are located on human chromosome six within the histocom­patibility complex. They share the same rece­ptors and about 30% homology at the amino acid level. However, there is sufficient structural difference that antibodies against TNF-α and TNF-β do not cross react. [29]

Interleukin-1 was the first described inter­leukin to mediate the effects of endotoxin. [30] It was known in 1960s and 1970s as "leucocytic endogenous pyrogen" and "leucocytic endo­genous mediator" because of its capacity to cause fever and elicit acute phase response. [30] IL-1 is a 17 KDa polypeptide and, like TNF, present in two forms; IL-l0 and IL-1F1 . Both peptides share many biological activities and are recognized by the same receptors, although they are products of different genes and share only 29% of the amino acid sequences. After its production, IL-lα remains mainly cell associated, whereas IL-1β is released and represents the soluble form. [31] Unlike the IL-lα precursor, the IL-1β precursor must be cleaved for optimal biologic activity. Several common enzymes cleave the precursor into smaller and more active forms, but IL-1β converting enzyme, which is an intracellular protease and a member of the cysteine protease family, is highly specific for cleaving IL-1β precursor from 31 KDa to its most active 17 KDa form. [32] This has been demonstrated by its substrate inhibitor, which reduced the amount of mature IL-1β produced by acti­vated monocytes. [33]

Anti-inflammatory Cytokines

Physiologically, the body system is equipped with another set of cytokines, including IL­ 4, [34] IL-6, [35] IL-10, [36] IL-13 [37] and transforming growth factor-β (TGF-β), [38] which are capable of suppressing and controlling inflammation, at least in part, by downregulating pro-inflam­matory cytokines such as TNF and IL-1. There are, however, other anti-inflammatory effects mediated by these cytokines. IL-4, for example, is capable of reducing LPS induced superoxide synthesis [39] and prostaglandin E2 [40] and appears to play an important role in allergy [41] and T-cell mediated immunity. [42] IL-10 upregulates monocytes production of IL-1 receptor antagonist [43] and protects mice from lethal endotoxemia. [44] IL-13 has also been shown to share many of IL-4 properties including inhibition of Thl-cells and enhance­ment of IL-1 receptor antagonist production. [43] Finally, in addition to its multiple immunosup­pressive effects and wound healing properties, [45] TGF-β also upregulates monocytes production of IL-6 [46] and IL-1 receptor antagonist [47] providing anti-inflammatory effects.

Cytokine Receptors

The biological effects of cytokines are mediated through their binding to specific receptors that are widely distributed. In case of TNF, there are two types of receptors that have been characterized biochemically and by reactivity with two sets of monoclonal antibodies. [48] These receptors are 55 (p55) and 75 (p75) KDa glycoproteins, which are differentially expressed on various cell lines. [49] The p55 is responsible for mediating most of TNF actions including cytotoxicity, antiviral activity and induction of mRNAs, whereas the function of p75 is probably mainly related to lymphocytic proliferation and maturation. [50] It is also likely that p75 detects low levels or concentrations of TNF and passes the signal to the more functionally active p55. One molecule of the trimer TNF (its native state) binds three extracellular domains of either p55 or p75. [51]

Interleukin-1 binds to an 80 KDa IL-1 receptor type-1 (IL-lRtl), which was originally found on T-lymphocytes and fibroblasts, [52] sub­sequently on almost all cell types and to a 60 KDa interleukin-1 receptor type-2 (IL-lRt2), which is found mainly on B-lymphocytes, monocytes/macrophages and neutrophils. [53] Although these two receptors differ structu­rally, [54] both forms of IL-1 can bind to them, with a higher affinity of IL-lα to IL-lRtl and IL-β to IL-lRt2. [55] However, other studies have shown that the biological effects of IL-1 are mediated through binding of IL-1 to its receptor type-1 (IL-lRtl). Binding to its receptor type-2 (IL-lRt2) acts as a decoy target for IL-1 and inhibits its activity. [56]

Soluble Cytokine Receptors and Natural Inhibitors

Inflammation is regulated and controlled not only by the anti-inflammatory cytokines but also by specific natural inhibitors. These include soluble receptors to TNF and IL-1 and an antagonist to IL-1 receptor.

The soluble receptors to TNF are p55 and p75 [29],[49] and for IL-1 p60 and p80. [57] Both kinds represent the truncated fragments of the extracellular domains of TNF and IL-1 receptors. Concentrations of soluble TNF receptors are increased in acute bacterial sepsis, malaria and acute and chronic hepatitis, as well as in chronic inflammatory diseases such as rheumatoid arthritis and systemic lupus erythematosus. [58] Similarly, soluble IL-1 receptors have also been found in different biological fluids and in different inflammatory conditions. [59] These inhibitors are believed to neutralize any excess of TNF and IL-1 and thus control the inflammatory response to injury. [49],[59]

The production of IL-1 is physiologically controlled and neutralized in vivo not only by its soluble receptors but also by a specific inhibitor to its membrane-bound receptor known as IL-1 receptor antagonist (IL-lra). IL-lra is an 18 KDa glycoprotein that shares 19% with the amino acid seuence of IL-α and 26% with that of IL-β. [61] It is produced by monocytes/macrophages [61] and polymor­phonuclear cells. [62] IL-lra has the capacity to neutralize the biological effects of IL-1 by specific binding to its receptors but without any agonist activity. [63],[64] Elevated plasma concentrations of IL-lra have been found in clinical experimental endotoxemia, where it exceeded those of IL-β by at least 100 fold. [65]5 mRNA for IL-lra can be detected both locally and systemically in vivo in models exposed to endotoxemia. [66] Recombinant human IL-lra has been found to block IL-1 [67] and LPS induced cytokine synthesis in vitro [68] and to reduce the local [69],[70] and systemic inflammatory effects [71],[72] of IL-1. Recently, IL-lra has been found to reduce the mortality in patients with septic shock. [59]


   Therapeutic Potential of Cytokines in Nephritis Top


Cytokines in Acute Glomerular

Inflammation

There is a large body of evidence to implicate cytokines in the pathogenesis of glomerulo­ nephritis: (1) TNF and IL-1, for example, are expressed in the glomeruli of rodents with experimental models of nephritis, and found in the biopsies, sera and urine of patients with different types of glomerulonephritis; [73],[74] (2) in vitro and in vivo studies document that both of these, and other, cytokines are produced locally within the inflamed glomeruli by mesangial and epithelial cells, as well as by infiltrating monocytes/macrophages; [75],[76] (3) systemic administration of TNF and IL-1 results in glomerular damage in rabbits; [77] (4) TNF and IL-1, like LPS, stimulate the acute phase response and hepatic synthesis of acute phase reactants, [78] and IL-6 is the major stimu­lant; [79] (5) an established acute phase response can influence and enhance the severity of experimental nephritis; [78] (6) either TNF, IL-1 or both, like LPS, exacerbates the degree of glomerular injury in nephrotoxic nephritis in rats; [80] (7) blocking endogenous TNF and IL-1, by polyclonal [81] or monoclonal anti­ bodies, [82],[83] or by their natural inhibitors, sTNFr, sIL-lRtl and IL-lra [84] in experimental nephritis ameliorates acute glomerular inflam­mation, manifested by a significant reduction in the magnitude of proteinuria, prevalence of glomerular capillary thrombosis and degree of glomerular inflammatory cell infiltrate. These effects were associated with down regu­lation of glomerular gene expression of the neutrophil chemoattractant protein (MIP-2) and monocyte chemoattractant protein-1 (MCP-1). [85] In addition, blocking these cyto­kines downregulates glomerular IL-0 mRNA expression and circulating TNF-0 concen­trations. [84],[86] Furthermore, similar effects were reproduced by pretreatment with type IV phosphodiesterase inhibitor, [87] IL-6, [88] and by continuous infusion of IL-6 in nephrotoxic nephritis. [89] Likewise, interleukin-4 ameliorates experimental glomerulonephritis and up-regu­lates glomerular gene expression of IL-1 decoy receptor. [90] These findings document the pivotal role of cytokines in acute glome­rular inflammation.

Cytokines in Chronic and Autoimmune

Glomerulonephritis

Bone morphogenic proteins (BMP) are members of the TGF-β superfamily. They regulate migration, proliferation and differen­tiation of pluripotent progenitor cells involved in the organogenesis. The kidney has been identified as a major site of BMP-7 synthesis. It is expressed with its receptors mainly in collecting ducts, proximal tubules and podo­cytes. Recent studies of knock out transgenic mice that are lacking BMP-7 failed to develop kidneys and died of uremia on the first postnatal day. [1] Injection of BMP-7 in experimental diabetic nephropathy resulted in reduction in proteinuria and restoration of GFR, with significant reduction in TGF-β production. This was associated with reversal of tubulo­interstitial fibrosis and normalization of glomerular histology. [92]

Experimental studies have documented the involvement of cytokines, and in particular TNF, in the pathogenesis of different models of autoimmune disease. [93] These include collagen induced arthritis, experimental auto­immune encephalitis, experimental autoimmune uveitis, type-I insulin dependent diabetes mellitus and autoimmune glomerulonephritis. [94],[95] Clinically, blocking TNF has been shown to be effective in controlling resistant sarcoidosis and allowed to reduce cortico­steroids regimen with no need for additional immunosuppressive treatment. [96] Clinical trials in rheumatoid arthritis [97] and chronic inflammatory bowel disease [98] have shown that neutralisation of endogenous TNF controls progression of the disease, and reduce produ­ction of other cytokines.

Previous studies in an experimental model of crescentic glomerulonephritis [99] have shown that short treatment with sTNFr p55 or monoclonal antibody to TNF caused a marked reduction in albuminuria and fibrinoid necrosis. It also reduced glomerular cell infil­tration, activation and proliferation. [100] Furthermore, prolonged treatment with sTNFr p55 caused sustained reduction in albuminuria and all the histological and cellular parameters of glomerular inflammation; in particular it completely prevented the development of cres­cents. In addition, administration of sTNFr p55 after induction and establishment of nephritis significantly reduced albuminuria and glomerular inflammation, including the prevalence of crescent formation. These findings were associated with less glomerular expre­ssion of IL-β and lower serum concentrations of IL-β in the sTNFr p55 treated rats, [100] More recently, the 'ACTIVE' trial open label multi-centre study that was conducted in patients with acute and persistent ANCA associated systemic vasculitis have shown that blockade of TNFα , by a monoclonal anti­body (infliximab), was effective at inducing remission and permitted reduction in steroid dose. [101] Furthermore, the urinary level of the monocyte chemoattractant protein-1 (MCP-1) has been shown to be a useful marker for renal inflammation in ANCA associated vascu­litis, [102] and in monitoring activity of lupus nephritis. [103] These findings clearly document the important role of TNF, and other cytokines, in chronic and autoimmune glomerulonephritis.

Role of Genetically Modified Macrophages

Macrophages are a main source of pro- and anti-inflammatory cytokines. They infiltrate the renal parenchyma in all types of renal injury, and their number correlates with the intensity of inflammation and renal injury. This was confirmed by depletion studies, [104] and more recently by repletion with intra­venously injected bone marrow-derived macro­phages. [105] There is marked macrophage heterogeneity and diversity of responses and functions depending on the nature of the stimulus/injury (immune or non-immune) and location within the kidney (glomerular or interstitial). For example, glomerular macro­phages in ANCA positive vasculitis express different activation markers from those in patients with cryoglobulinemic glomerulo­nephritis. [106] Glomerular macrophages also express different chemokine receptors from interstitial macrophages in severe proliferative glomerulonephritis and in renal transplant rejection. [107] Furthermore, macrophages stimu­lated by INF-γare capable of secreting pro­inflammatory cytokines and respond by killing microorganisms, whereas macrophages stimu­lated by IL-4 and IL-13 produce anti-inflam­matory cytokines such as IL-lra and IL-10 and develop regulatory functions. On the other hand, macrophages stimulated by immune complexes secrete TNF, IL-6 and IL-10 and can posse immunosuppressive effects and tissue repair. [108}

Different experimental studies have shown that macrophage function is determined by the initial cytokine contact, which induces 'programmed' unresponsiveness to subsequent cytokines. There is a hierarchy when macro­phages are exposed to two cytokines simulta­neously, e.g. INF-γ dominates over TNF-α and TGF-β . The studies of genetically modified macrophages transduced by recombinant adenovirus to express different cytokines including IL-4 and IL-10 [109] and IL-lra [110] and injected systemically into rats with NTN were localized to inflamed glomeruli, produced the cytokines in vivo and reduced albuminuria and histological markers of glomerular inflam­mation. This was associated with a decrease in the macrophage infiltration and expression of activation markers MHC class II and ED3. [111] More recently the Rees group [108]

has shown that injection of IL-4 and IL-10­expressing macrophages into the renal artery of rats with NTN resulted in highly effective localization to the glomeruli of the injected kidney and very low numbers in the contra­lateral kidney. This was associated with an attenuation of inflammation in the contralateral kidney. Thus local manipulation of macro­phages to release certain cytokines(s) provides a powerful tool to control glomerular inflam­mation and systemic immune response.

Hematopoietic Stem Cells

It is believed that in response of the mesan­gium to injury hematopoietic progenitor stem cells migrate into injured glomeruli and get involved in the normal turnover of mesangial cells. [112] The migration and proliferation of these cells are controlled by certain growth factors such as PDGF and b-FGF. The PDGF plays an important role in the migration of the progenitor cells into the glomerulus, whereas bFGF has been linked to the proliferation of repopulating mesangial cells. [113] Recent studies of experimental bone marrow transplantation from normal mice into those producing high circulating IgA levels and are prone to IgA nephropathy led to a resolution of the glome­rular sclerotic changes, [114] Furthermore, human [115] and experimental [116] studies have demonstrated the presence of bone marrow­derived cells within regenerating tubules. In a model of ischemia/reperfusion injury in rats, El Nahas group have observed a significant infiltration of regenerating tubules by CD34+ hematopoietic cells. [117] Thus, it appears that there are certain cytokines/growth factors that are responsible for attraction (or inhibition) of the hematopoietic progenitor stem cells to repopulate injured glomeruli and tubules. Furthermore, characterization of the different types of these cytokines/growth factors, and/ or isolation and growth of the relevant stem cells carries an important and rather specific therapeutic potential in regenerating glomerular and interstitial damage following renal inflammation.

In conclusion, cytokines and growth factors play an important role not only in the ini­tiation and amplification of glomerular injury, but more importantly in controlling inflammation and remodelling process. A better understanding of their regulatory mechanisms and the appropriate ways of their application may lead to new and specific therapeutic measures.

 
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Correspondence Address:
Ayman Karkar
Kanoo Kidney Centre, Dammam Central Hospital, P.O. Box 11825, Dammam 31463
Saudi Arabia
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