This novel observation, together with published evidence of chemotaxis activity by IL-17 on airway smooth muscle cells[23], suggests the possibility that other structural or innate/adaptive immune cells could display chemotactic response to Th-17-derived cytokines; if this hypothesis is true, the impact of Th-17 cytokines in asthma pathophysiology and in other chronic inflammatory diseases could have been underestimated. of healthy subjects. Using an in-vitro migration assay, B cells were shown to migrate towards both IL-17A and IL-17F. Interestingly, blocking IL-17A and IL-17F signaling using either anti-IL-17R antibodies or MAP kinase inhibitors prevented in vitro migration of B cell towards IL-17. These observations indicate a direct chemotactic effect of IL-17 cytokines on primary peripheral blood B cells with higher effect being on asthmatic B cells. These findings revealed a key role for IL-17 in enhancing the migration of B cells to the lung tissue during asthma or COPD. == Introduction == Th-17 cells and their characteristic cytokines IL-17A, IL-17F, IL-21 and IL-22 play a beneficial role in the host-defense response against extracellular bacterial and fungal pathogens. However, they are also major harmful promoters in the pathogenesis of many chronic autoimmune and allergic disorders, including inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and allergic asthma[1][3]. Thus, Th17-derived IL-17A and IL-17F are at the basis of many diseases, and their effects are complex and multiple; in particular, these cytokines can induce the release Rabbit Polyclonal to MSH2 of various pro-inflammatory mediators including chemokines, cytokines, and metalloproteinases in many cell targets[4][8]. Inflammation of the airways in asthmatics is promoted by a number of cytokines, chemokines, prostaglandins and other mediators secreted by inflammatory cells (e.g., lymphocytes, granulocytes) and by structural cells (e.g., airway epithelial, smooth EMD534085 muscle cells). Yet, the pathophysiology of asthma differs considerably among patients; such differences, observed in the degree of severity of asthma symptoms, are believed to be determined by the predominant pro-inflammatory cytokine profile in the airways patients[9][11]. For instance, most patients with well controlled asthma symptoms typically exhibit a prevalent eosinophil infiltration in the airway tissues, along with detectable Th-2-derived cytokines (IL-2, IL-4, IL-5 and IL-13)[9],[12]. In contrast, asthmatics with refractory asthma symptoms present generally a significant infiltration of neutrophils in the airways, and detectable levels of Th-17-associated cytokines (IL-17A, IL-17F, IL-21)[4],[6],[10],[11],[13]; in these patients, a preferential infiltration of neutrophils over eosinophils EMD534085 is driven by IL-17-stimulated airway epithelial cells via p38 MAPK, and release the chemokine CXCL8 (IL-8) that promotes granulocyte recruitment, particularly neutrophils[5],[14][15]. In vitro experiments also support the possibility that IL-17 could, directly or indirectly, support the recruitment of IgE+ antibody-secreting B cells in the airways, by stimulating airway epithelial cells to produce CCL28 chemokine[8]. These observations are in agreement with those obtained from a mouse model, in which adoptively transferred subset of T cells expressing the inducible T-cell costimulator (ICOS) that is critical for the expansion of Th-17 cells, promoted a remarkable infiltration of both T and IgE-allergen specific B cells in lung tissues[16][17]. IL-17A and IL-17F cytokine signaling is mediated by specific receptors composed of IL-17RA and IL-17RC subunits, which are expressed on the cell surface of many cell types, including airway epithelial, airway smooth muscle and microvascular airway endothelial cells[14],[18][23]. Recent in vitro evidence suggested that IL-17A and IL-17F cytokines can also regulate airway smooth muscle (ASM) cell migration by an autocrine mechanism that involves the upregulation of growth-related oncogene (GRO) family of chemokines (GRO-a/CXCL1, GRO-b/CXCL2, GRO-g/CXCL3)[24]. Importantly, it was EMD534085 also shown in vitro that IL-17A, IL-17F and IL-22 cytokines could exert a direct chemotactic activity on airway smooth muscle (ASM) cells; hence, augmented ASM cell mass EMD534085 and tissue remodeling of the airways in severe asthma and COPD patients could be explained in part, by the infiltration of ASM cells elicited by Th-17-associated cytokines[23]. Also, among the adaptive immune cells, B lymphocytes express high levels of IL-17RA receptors, and therefore respond to Th-17-derived cytokine stimulations[25]. Hence, IL-17 modulates B cell activation and promotes its proliferation[7],[26][27]. Th-17 cytokines also stimulate Ig isotype switching by upregulating activation-induced cytidine deaminase (AICD) gene expression, and enhance the production of autoantibodies in a rheumatoid arthritis (RA) BXD2 mouse model[26],[28]. Importantly, IL-17 cytokines coordinate the timely sequestration of responder B cells within the follicular light zone of germinal centers (GC), via upregulation of the regulators of G-protein signals (RGS) Rgs13 and Rgs16, thus suppressing B cells chemotactic response to CXCL12 and CXCL13, and ensuring their interaction with follicular Th cells to promote B cell differentiation into autoantibody-producing plasma B cells in a RA BXD2 mice model[21],[28]. Similarly, the development of lung ectopic lymphoid tissues containing B cell follicles during infection (e.g., tuberculosis) or chronic inflammation (e.g., rheumatoid arthritis, COPD), is driven by CD4+ Th-17 cells and associated IL-17 cytokines, by promoting.