Interleukin-17 is a negative regulator of established allergic asthma

T helper (Th)17 cells producing interleukin (IL)-17 play a role in autoimmune and allergic inflammation. Here, we show that IL-23 induces IL-17 in the lung and IL-17 is required during antigen sensitization to develop allergic asthma, as shown in IL-17R–deficient mice. Since IL-17 expression increased further upon antigen challenge, we addressed its function in the effector phase. Most strikingly, neutralization of IL-17 augmented the allergic response in sensitized mice. Conversely, exogenous IL-17 reduced pulmonary eosinophil recruitment and bronchial hyperreactivity, demonstrating a novel regulatory role of IL-17. Mechanistically, IL-17 down modulated eosinophil-chemokine eotaxin (CCL11) and thymus- and activation-regulated chemokine/CCL17 (TARC) in lungs in vivo and ex vivo upon antigen restimulation. In vitro, IL-17 reduced TARC production in dendritic cells (DCs)—the major source of TARC—and antigen uptake by DCs and IL-5 and IL-13 production in regional lymph nodes. Furthermore, IL-17 is regulated in an IL-4–dependent manner since mice deficient for IL-4Rα signaling showed a marked increase in IL-17 concentration with inhibited eosinophil recruitment. Therefore, endogenous IL-17 is controlled by IL-4 and has a dual role. Although it is essential during antigen sensitization to establish allergic asthma, in sensitized mice IL-17 attenuates the allergic response by inhibiting DCs and chemokine synthesis

Dual role of Th17 cytokines, IL-17A,F, and IL-22 in allergic asthma

The proinflammatory role of T helper (Th) 17 cells and therefore of its cytokines, IL-17 (IL-17A), IL-17F, and IL-22, in autoimmune disorders has been favored, although there is evidence that not only IL-17A but also IL-17F and IL-22 have a dual role as negative regulators. Here we review the concept of the dual function of IL-17A, IL-17F, and IL-22 in the light of recent strategies to use neutralization of these cytokines as potential alternative to neutralizing TNF and IL-1 treatments in chronic inflammatory disorders. Expectedly, in allergic lung inflammation, neutralization of IL-17A inhibited neutrophil recruitment. However, this IL-17A antibody treatment concomitantly increased eosinophil recruitment by neutralizing IL-17A’s dual role as negative regulator. IL-17A negatively regulated dendritic cell function and activation of T helper cell (Th)2 cytokine production. Furthermore, IL-17A inhibited Th2-characteristic chemokine and adhesion molecule expression. On a mechanistic level, IL-17A acted on IκB-β by preventing degradation and in turn leading to reduced NF-κB activation or IL-17A inhibited transcription factor IRF-1. Therefore, anti-IL-17A therapy, although presenting a promising lead in chronic inflammatory disorders, bears a potential risk of exacerbating allergic asthma

Dual role of IL-17 in allergic asthma

A proinflammatory role of IL-17 in autoimmune disorders has been favored, although there is evidence that IL-17 has a dual role as negative regulator. Here we review the concept of dual IL-17 functions in the light of recent strategies to use IL-17 neutralization as potential alternative to neutralizing TNF and IL-1 treatments in chronic inflammatory disorders. Expectedly, in allergic lung inflammation, neutralization of IL-17 inhibited neutrophil recruitment. However, this IL-17 antibody treatment concomitantly increased eosinophil recruitment by neutralizing IL-17’s dual role as negative regulator. IL-17 negatively regulated dendritic cell function and activation of T helper cell (Th)2 cytokine production. Furthermore, IL-17 inhibited Th2-characteristic chemokine and adhesion molecule expression. On a mechanistic level, IL-17 acted on IκB-β by preventing degradation and in turn leading to reduced NF-κB activation or IL-17 inhibited transcription factor IRF-1. Therefore, anti-IL-17 therapy, although presenting a promising lead in chronic inflammatory disorders, bears a potential risk of exacerbating allergic asthma

Interleukin-22 is a negative regulator of the allergic response

A proinflammatory role of T helper (Th)17 cells, producing IL-22 and IL-17A, has been favored although there is evidence for negative immune regulation by IL-17A. Here we show that IL-22 was produced during an allergic response in lungs of mice, immunized and challenged with ovalbumin (OVA), and that IL-22 neutralization further augmented the eosinophil recruitment to the lung. In a second allergy model, transfer of OVA-pulsed dendritic cells (DC) into naive mice conveyed eosinophil recruitment in response to subsequent inhaled OVA challenge, while DC preincubation with recombinant IL-22 abolished this response. Similarly, DC preincubation with IL-17A abolished DC-driven eosinophil recruitment, showing that both Th17 cytokines IL-22 and IL-17A mediate negative regulation of allergy by acting on DCs. Therefore, IL-22 inhibits DC functions and attenuates an allergic response

Regulation and function of the CXC chemokine ENA-78 in monocytes and its role in disease.

Epithelial neutrophil-activating protein 78 (ENA-78) is a member of the CXC chemokines and acts as a potent chemoattractant and activator of neutrophil function. On stimulation in vitro, ENA-78 is highly expressed in many cell types. ENA-78 protein levels are strongly elevated in synovial fluid and blood of patients with rheumatoid arthritis. By in situ hybridization and immunofluorescence staining, ENA-78 has been recognized as a major CXC chemokine expressed in epithelial cells of the intestinal mucosa of patients with Crohn's disease, ulcerative colitis, and acute appendicitis. A high expression of ENA-78 and interleukin-8 (IL-8) was also observed in the exocrine tissue of patients with chronic pancreatitis (CP). It is interesting to note that expression of IP-10, MIP-1alpha, and MCP-1 is high in healthy pancreatic tissue but low in tissue of patients with CP, suggesting a mutually exclusive expression of the ELR-CXC vs. non-ELR-CXC/CC chemokines. High-resolution studies of intracellular chemokines has revealed specific immunoreactivity for ENA-78 associated with the endoplasmic reticulum of many cell types. In contrast, GROalpha immunoreactivity was exclusively localized in the nucleus. Despite their common effects on neutrophil functions, the differential intracellular localization of ENA-78 and GROalpha suggests additional roles for these two chemokines in normal cell biology

Regulation and function of the CXC chemokine ENA-78 in monocytes and its role in disease

Epithelial neutrophil-activating protein 78 (ENA-78) is a member of the CXC chemokines and acts as a potent chemoattractant and activator of neutrophil function. On stimulation in vitro, ENA-78 is highly expressed in many cell types. ENA-78 protein levels are strongly elevated in synovial fluid and blood of patients with rheumatoid arthritis. By in situ hybridization and immunofluorescence staining, ENA-78 has been recognized as a major CXC chemokine expressed in epithelial cells of the intestinal mucosa of patients with Crohn's disease, ulcerative colitis, and acute appendicitis. A high expression of ENA-78 and interleukin-8 (IL-8) was also observed in the exocrine tissue of patients with chronic pancreatitis (CP). It is interesting to note that expression of IP-10, MIP-1alpha, and MCP-1 is high in healthy pancreatic tissue but low in tissue of patients with CP, suggesting a mutually exclusive expression of the ELR-CXC vs. non-ELR-CXC/CC chemokines. High-resolution studies of intracellular chemokines has revealed specific immunoreactivity for ENA-78 associated with the endoplasmic reticulum of many cell types. In contrast, GROalpha immunoreactivity was exclusively localized in the nucleus. Despite their common effects on neutrophil functions, the differential intracellular localization of ENA-78 and GROalpha suggests additional roles for these two chemokines in normal cell biology

Interferonâ α and interferonâ γ downâ regulate the production of interleukinâ 8 and ENAâ 78 in human monocytes

The two chemotactic cytokines interleukinâ 8 (ILâ 8) and epithelial neutrophil activating protein 78 (ENAâ 78) were recently shown to be potent chemoattractants and activators of neutrophil function and to be present in certain inflammatory diseases. We have studied the effects of recombinant and natural interferonâ α (IFNâ α) and of recombinant interferon gamma (rIFNâ γ) on the production of ELâ 8 and ENAâ 78 in lipopolysaccharideâ and interleukinâ 1â stimulated human monocytes. Both types of interferons showed a strong, concentrationâ dependent inhibition of neutrophilâ stimulating bioactivity. Similarly, the secretion of ILâ 8 and ENAâ 78 was also inhibited by up to 73%. Northern blot experiments demonstrated that IFNâ α decreases the steadyâ state levels of ILâ 8 and ENAâ 78 mRNA in monocytes, suggesting that IFNâ α as well as IFNâ γ may control the expression of neutrophil chemotactic cytokines at the mRNA level. J. Leukoc. Biol. 57: 929â 935; 1995.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141988/1/jlb0929.pd