This article gives an overview of Interleukin 17 (IL-17) examining its origins and the role it plays in inflammation and various bacterial and viral diseases. A comparison to human IL-17 biology is included to provide further understanding of this cytokine.

Introduction

IL-17 specifically IL-17A, was discovered in 1993 originally as cytotoxic T lymphocyte-associated antigen 8 (CTLA8) in a rodent T cell cDNA transcript (Rouvier et al. 1993). In 1995, human IL-17 was identified as a new cytokine, mainly originating from activated CD4+ T cells (Yao et al. 1995). This cytokine was found to stimulate human fibroblasts to secrete IL-6, IL-8, and upregulate ICAM-1 expression. IL-17A has a protective role against bacterial and fungal infections by recruiting neutrophils to the infected area. IL-17A also modulates the pathology of autoimmune disease e.g. experimental autoimmune encephalomyelitis (EAE), arthritis (Benedetti and Miossec 2014), systemic lupus erythematosus (SLE), graft versus host disease (GVHD) (Tabarkiewicz et al. 2015), and inflammatory bowel diseases (IBD) (Kanai et al. 2012).


The IL-17 cytokine family

The IL-17 family is made up of six members: IL-17A (commonly known as IL-17), IL-17B, IL-17C, IL-17D, IL-17E (commonly known as IL-25), and IL-17 F (Gaffen 2009). The biological function and regulation of IL-17A and IL-17F have benefitted from deeper investigations than the remainder of the IL-17 cytokine family. In mouse and human, IL-17A and IL-17F reside on the same chromosome reflecting their shared expression pattern. IL-17A and IL-17F encode proteins of 155aa and 163aa, respectively, and share the highest amino acid sequence homology (50%). Both IL-17A and IL-17F mediate proinflammatory responses by inducing fibroblasts, endothelial cells, and epithelial cells to express genes encoding proinflammatory cytokines (IL-1, IL-6, TNF, GM-CSF and G-CSF), chemokines (CXCL1, CXCL5, IL-8, CCL2 and CCL7), antimicrobial peptides (S100 proteins and defensins), and matrix metalloproteinases (MMP1, MMP3 and MMP13).

IL-17A is a key modulator of host defenses against bacterial and fungal infections but is also involved in the development of autoimmunity, inflammation, and tumors. IL-17F predominates in mucosal host defense mechanisms, i.e. host defense against bacteria and inflammation in epithelial tissues (Iwakura et al. 2011).

With the exception of IL-17E, which is involved in promoting a Th2 cell-type immune response, IL-17A, IL-17B, IL-17C, and IL-17F can trigger the secretion of proinflammatory cytokines (e.g. TNF and IL-1β) from fibroblasts and induce neutrophil migration, suggesting a role in disease development. IL-17 is secreted by activated CD4+αβ T cells, CD8+αβ T cells, NKT cells, γδ T cells, macrophages and neutrophils. It plays a key role in inflammation by directing migration of neutrophils into tissues and increases chemokine production (Jin and Dong 2013).


Th17 cells

Upon activation, CD4+ T cells expand and develop into three T helper subsets (Th1, Th2, and Th17 cells) with different effector functions and different cytokine profiles. Th1 cells mainly produce IFN-γ alongside IL-2, TNFα, and lymphotoxin alpha (LT-α) and the transcription factor T-bet. Th2 cells secrete IL-4, IL-5, IL-13 and express the transcription factor GATA-3. CD4+ Th17 cells secrete IL-17A, IL-17F, IL-22 as well as GM-CSF and other cytokines (TNF, IFN-γ, IL-21, and IL-26), and the transcription factor ROR-γt.

Th17 differentiation is driven by transforming growth-factor beta (TGF-β), IL-1 and IL-6. IL-23 is needed to stimulate, expand and stabilize IL-17 production. Th17 cells are characterized by the transcription factors RORγt, RORα, and STAT3. During infection, Th17 cells are the first T cell subset that is generated (Korn et al. 2009).

Th17 responses are defined by the production of IL-17 and play a critical role in inflammatory responses. In mouse and human, γδ T cells have been shown to produce key quantities of IL-17 in certain diseases (O’Brien et al. 2009).

In contrast, in cattle, two distinct populations of IL-17+ T cells have recently been shown to produce IL-17 in response to infection, CD4+Th17 and γδ 17 T cells (Flynn and Marshall 2011 and Peckham et al. 2014). Similar to mouse and human, IFN-γ downregulates IL-17 production of bovine CD4+Th17 and γδ 17 T cells. Additionally, bovine CD4+Th17 cells have high levels of CCR6 and IL-23R expression, as also observed in human and mouse. However, bovine γδ 17 T cells do not express these molecules suggesting that these γδ 17 T cells do not respond to IL-23 and are, therefore, unable to undergo the stabilizing process that CD4+Th17 cells undergo.


Human IL-17 biology

In humans, CD4+ Th17 cells produce IL-17A, IL-17F and IL-22 (in addition to GM-CSF and other cytokines). Regulatory Th17 (rTh17) cells secrete IL-17A and IL-10 and downregulate canonical TH17 cells. Innate lymphoid cells (ILC) express most of the IL-17A and IL-22 found in the intestines. Finally, γδ T cells are similar to Th17 cells in their cytokine behavior, so are a good source of IL- 17A and IL17F (Jones et al. 2012).

IL-17A and IL-17F are key modulators in the defense against microbes but they also contribute to tissue destruction that occurs in chronic inflammation and autoimmune diseases such as rheumatoid arthritis (RA), psoriasis, and multiple sclerosis. RA patients exhibit an increase serum level of IL-17 (5 to 8 fold increase) and the percentage of Th17 cells is significantly elevated compared with control patients (Al-Saadany et al. 2016).

IL-17 is also involved in the pathogenesis of respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD) (Jones and Chan 2002). In asthmatics, IL-17 is upregulated, as indicated by elevated levels of serum IL-17 and lung IL-17 mRNA and protein. This upregulation of IL-17 drives neutrophilic inflammation. IL-17A increases IL-8 and GM-CSF production in human airway epithelial cells, but only when acting synergistically in concert with TNF-α or IL-1β (Honda et al. 2016).

The IL-17-Th17 pathway is regulated by IL-23, so using inhibitors to target IL-23, IL-17A or IL-17 receptors, could be used to develop new therapies to target this pathway to reduce inflammation (Jones et al. 2012, Bosmann and Ward 2012). However, targeting IL-17 or the cells that produce IL-17 could increase the risk of bacterial and fungal infections (Robinson et al. 2013).

IL-17, in its role as an early initiator of inflammation, stimulates the production of several proinflammatory mediators in fibroblasts, osteoblasts, synoviocytes, chondrocytes, macrophages, endothelial, and epithelial cells. These inflammatory mediators cause neutrophils (CXCL8, CXCL5, CCL5, CXCL1, and its homolog CINC, ICAM-1), lymphocytes (CCL20, CXCL10, CCL2, CCL5), or other immune cells (CXCL2, CXCL10, CCL2, CCL5) to migrate to the site of inflammation. This immune response is further enhanced and amplified by IL-17 driven stimulation of macrophages and other cell types to produce TNFα, IFN-γ, and IL-1β (Benedetti and Miossec 2014).

T regulatory (Treg) cells and Th17 cells develop from naïve CD4+ precursors in response to induction by transforming growth factor b1 (TGFβ1). Th17 is a key effector cell of autoimmune disease while Treg cells induce immunologic tolerance. An imbalance between Th17 and Treg cells is thought to lead to tissue inflammation. Evidence for involvement of Th17 cells in organ specific autoimmune disease comes from findings that deletion of the p19 chain of IL-23 (a cytokine crucial for Th17 cell growth) in EAE and collagen-induced arthritis resulted in the absence of Th17 cells and protection from disease (Eisenstein and Williams 2009).


IL-17 role in bovine disease

BRSV (Bovine respiratory syncytial virus)

BRSV is genetically related to human respiratory syncytial virus (HRSV). Both BRSV and HRSV cause severe respiratory infections in young cattle and children. Children infected with HRSV have increased IL-17 and Th17 responses, which are involved in protective and pathogenic roles during infection.

Recently, and for the first time, IL-17 and Th7 responses have been demonstrated in BRSV infected calves (McGill et al. 2016). The infected calves have higher levels of IL-17, IL-21, and IL-22; CD4+ T cells and γδ T cells are key to this response. BRSV infected cattle can also develop BRDV if they go on to show signs of bacterial pneumonia caused by pathogens such as Mannheimia haemolytica. This co-infection (primary viral infection followed by bacterial infection) drives increased IL-17 production, mainly by γδ T cells.

Mastitis

Environmental pathogens are ubiquitous and difficult to eliminate. The pathogens usually reside in the mammary gland of infected cattle and can infect other cows during milking. Microbes from the surrounding environment can also lead to infection during milking. Mastitis is caused by Escherichia coli (E. coli) and Staphylococcus aureus. Recent research has found that IL-17A and IL-17F genes are induced during E. coli infections (Roussel et al. 2015).

Mycobacterium bovis (M. bovis)

M. bovis is the causative agent of tuberculosis in cattle but also infects other animals, including humans. Bovine tuberculosis (bTB) not only affects the development of the dairy and meat industries but also infects a wide range of hosts: deer, llamas, cats, rodents, possums, mustelids, foxes and coyotes.

Delayed-type hypersensitivity skin test and IFN-γ release assays diagnostic tests are used to diagnosis bTB in cattle. However, test responses do not correlate with disease severity. There is a need for markers to discriminate tuberculin positive cattle that have tuberculosis lesions from those that don’t have lesions. Also, protection against bTB using the Bacillus Calmette-Guérin (BCG) vaccine is not complete. However, cattle vaccinated with BCG overexpressing AG85B showed higher production of IL-17 and IL-4 mRNA when their peripheral blood mononuclear cells (PBMCs) were challenged with purified protein derivative (PPDB), in comparison to BCG vaccine recipients. Furthermore, post vaccination IL-17 mRNA expression showed a negative correlation with disease severity during a subsequent infection with M. bovis; suggesting that IL-17 is a potential biomarker of cattle protection against bovine tuberculosis (Rizzi et al. 2012, Waters et al. 2015).

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