Cytokines and chemokines are key modulators of immune responses and play diverse roles in inflammatory diseases. Here, we discuss the role of specific cytokines and chemokines in inflammatory bowel disease (IBD) and nephritis.
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Inflammatory bowel disease, a multifactorial disease with unknown etiology, is comprised of two major subtypes: ulcerative colitis (UC) and Crohn’s disease (CD). UC primarily affects the large intestine or colon, while CD may affect any part of the gastrointestinal tract (1). One of the many attributed reasons for IBD is an inappropriate immune response triggered by genetic and environmental factors. Studies in recent years have identified that cytokines IL-23, IL-12, IL-17, and IL-10 play pivotal roles in IBD pathogenesis (7-9). IL-12 and IL-23, which are abundantly expressed in the small intestine, are hypothesized to be essential in maintaining intestinal barrier homeostasis (2). Patients with specific IL-23 receptor variants have exhibited an increased risk of developing IBD (2). Furthermore, mouse models of IBD have shown a decrease in gut inflammation through suppression of these cytokines. While clinical treatment for IBD usually relies on anti-inflammatory drugs, including TNF-α inhibitors, the Food Drug Administration (FDA) has approved a new therapeutic for targeting the p40 subunit of IL-12/IL-23 (1,3).
In contrast to the therapeutic benefits of IL-12/IL-23 targeted drugs, clinical studies focused on inhibitory drugs targeting IL-17 showed no benefit for IBD patients. Although data shows upregulation of IL-17 by the gut microbiome in IBD patients, blocking the IL-17 pathway failed to improve IBD symptoms. The current hypothesis for IL-17 involvement in the disease is that the upregulation of the IL-17 is due to intestinal microbiome interactions, which might depend on IL-17 signaling for homeostasis (3).
Further supporting the role of the intestinal microbiome in IBD, a recent publication focusing on serological biomarkers of CD shows high titers of antibodies to intestinal commensal proteins, including outer membrane porin C (OmpC) of Escherichia coli. This study also shows that immune cells from CD patients have downregulated IL-10 expression compared to healthy controls. Given the pivotal role of IL-10 in immunoregulation of the gastrointestinal tract, downregulation of IL-10 suggests a defect in immune responses towards intestinal microbiome (4).
CCL28 is an epithelial chemokine associated with the GI mucous membrane, making it a promising target for IBD research. Another study used the ELISA technique to compare CCL28 levels in UC patient serum with healthy individuals. The study concluded that there are increased levels of CCL28 in UC patients and that CCL28 should be considered as a diagnostic tool for IBD (5). Other studies using the serum of IBD patients have shown elevated CCL2, CCL20 and CCL25 (6,7). However, more research is needed to determine the therapeutic potential of these chemokine targets.
One of the most popular and well characterized mouse models of IBD is the dextran sulfate sodium (DSS)-induced colitis model. Studies using DSS-induced colitis have shown that CCL20 expression is upregulated in the dome epithelium of Peyer’s patches and on the surface epithelial cells. When CCL20-CCR6 interaction is blocked by administration of anti-CCL20 antibodies, mice showed a reduction in gut inflammation and were resistant to the induction of colitis by DSS (7,8). Another study elicited colitis with DSS and assessed colon permeability with Chondrex, Inc.’s FITC-Dextran. The group was studying the therapeutic effects of an andrographolide-lipoic acid conjugate (AL-1) and concluded that AL-1 alleviated DSS-induced colitis and maintained the intestinal mucosa barrier function. They assessed the inflammatory response by measuring expression levels of TNF-α, IL-6, IL-1β and IL-10 by ELISA. Treatment with AL-1 lowered the pro-inflammatory cytokines and elevated IL-10 in a dose dependent manner (9).
Jiang N, Wei Y, Cen Y, Shan L, Zhang Z, Yu P, Wang Y, Xu L. Andrographolide derivative AL-1 reduces intestinal permeability in dextran sulfate sodium (DSS)-induced mice colitis model. Life Sci. 2020 Jan 15;241:117164. PMID: 31838135.
Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in humans. MN is characterized by inflammation and renal failure, including proteinuria due to the accumulation of immune complexes along the glomerular basement membrane (GBM). Recent advances in the field have shown that around 75% of patients elicited serum antibodies against the phospholipase A2 receptor (PLA2R) present in podocytes, which are essential cells for blood filtration. Elevated serum levels of inflammatory cytokines, such as TNF-α, IL-4, IL-5, IL 10, IL-2, and IFN γ, are also seen in MN patients (10-12). Interestingly, patients also showed decreased serum IL-17 and IL-6 levels when compared to healthy individuals (12, 13).
One of the key pathological characteristics of nephritis is the loss of podocyte cells in the kidneys, ostensibly caused by upregulation of CXCL12. In mouse models of MN, CXCL12 can suppress Notch signaling, an important regulator of the progenitor-podocyte differentiation pathway. Inhibition of CXCL12 by NOX-A12, both in vitro and in vivo, successfully reversed podocyte loss and reduced proteinuria (14).
A recent study by Lui, Y et al. used Chondrex, Inc.’s cationic bovine serum albumin (cBSA) to induce ICGN nephritis and test the therapeutic efficacy of Isoliquiritin (ILQ), a flavonoid with anti-inflammatory properties, on kidney dysfunction. The study highlights the therapeutic effects of ILQ by showing that it ameliorates proteinuria and pathological changes of the rat kidney. In addition, the team analyzed protein expressions of TNF-α and IL-1β by ELISA, which showed reduced concentrations after ILQ treatment (15).
Several other methods are used for inducing experimental autoimmune nephritis, including immunization with nephritogenic NC1 fragments or anti-GBM monoclonal antibodies. To learn more about these models and their unique features, follow the link above.
Y. Liu, X. Xu, R. Xu, S. Zhang, Renoprotective Effects Of Isoliquiritin Against Cationic Bovine Serum Albumin-Induced Membranous Glomerulonephritis In Experimental Rat Model Through Its Anti-Oxidative And Anti-Inflammatory Properties. Drug Des Devel Ther 13, 3735-3751 (2019).