Interleukin-17A and Interleukin-17F: A Tale of Two Cytokines

Children's Hospital of Pittsburgh, Rangos Research Center, Pittsburgh, PA 15201, USA.
Immunity (Impact Factor: 21.56). 02/2009; 30(1):9-11. DOI: 10.1016/j.immuni.2008.12.010
Source: PubMed


Charles Dickens's epic tale of Paris and London begins with “It was the best of times, it was the worst of times,” emphasizing the recent advances in wisdom that coincided with a time of great ignorance. In the past 10 years, our understanding of interleukin-17 (IL-17) in mucosal immunity and autoimmunity has greatly expanded. IL-17A, the founding member of the IL-17 family of cytokines, is produced by a subset of CD4+ T cells termed Th17 cells. IL-17A is potent inducer of antimicrobial peptides as well as neutrophil growth factors such as granulocyte colony-stimulating factor (G-CSF) and it also mediates host resistance to extracellular bacterial and fungal infections. An unintended consequence of this arm of the immune system is autoimmunity. To this end, Th17 cells have been shown to be critical mediators of many autoimmune disorders. However, the individual contributions of the two most closely related IL-17 family members, IL-17A and IL-17F (which share 55% homology at the amino acid level), and the role of their receptors in these processes has been an area of needed enlightenment. The paper by Ishigame et al. (2009) in this issue of Immunity substantially expands our wisdom of the individual contributions of the ligands IL-17A and IL-17F (and their receptors IL-17RA and IL-17RC) in mucosal immunity and autoimmune tissue inflammation.

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    • "The contrasting biological functions could be due to an approximate 10-fold more potent induction of cytokines by IL-17A as compared to IL-17F [35]. In support of this concept, a recent review by Dubin and Kolls [36] has suggested a model which emphasizes the bioactivities of these cytokines on myeloid versus nonmyeloid cells or macrophages versus CD4+ T cells discussed priorly. Therefore, it is the ability of IL-17A to induce stronger responses and affect a wider range of cellular targets, making it a more pathogenic cytokine. "
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    ABSTRACT: Interleukin-17A (IL-17A) and IL-17F have been shown to mediate a crucial crosstalk between the immune system and various epithelial tissues, stimulating various defensive mechanisms to bacterial infections. A number of studies have characterized the response to IL-17A and IL-17F of epithelial cells from airways, intestine, and skin, but not from the mammary gland. To evaluate the potential contribution of IL-17 to the immune defense of the mammary gland, we analyzed the effects of recombinant bovine IL-17A and IL-17F on primary bovine mammary epithelial cells (MEC) by quantitative PCR and ELISA. We found expression (mRNA) of the two components of the IL-17 receptor complex, IL-17RA and IL-17RC, in mammary tissue and MEC in vitro. The expression of a number of genes encoding cytokines, chemokines and proteins endowed with antibacterial activities was increased by IL-17A, and to a lesser extent by IL-17F, but the magnitude of responses was modest. As expected, responses were augmented by the combination of IL-17A or IL-17F with TNF-α. Interestingly, responses of a few of the tested genes, such as IL8, CCL20, iNOS, and CfB, were augmented by the combination of IL-17A with staphylococcal lipoteichoic acid or muramyl dipeptide, bacterial agonists of the innate immune system. This can be interpreted as indicating that IL-17A and IL-17F are tailored to exert their full potential in a septic environment. MEC responses were characterized by the expression of chemokines targeting not only neutrophils (CXCL3 and CXCL8) but also mononuclear leucocytes (CCL2, CCL20). Production of IL-6 was low and the inflammatory cytokines TNF-α and IL-1β were expressed (mRNA) but proteins were not secreted. Altogether, our results suggest that IL-17A and IL-17F have a potential to modulate the mammary gland immune response to mastitis-causing pathogens.
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