Interleukin-19 Research Articles

Interleukin‐19 Can Simultaneously Reduce Atherosclerosis and Increase Perfusion in Hind Limb Ligated LDLr−/− Mice

Peripheral arterial disease is often a co‐morbidity with hypercholesterolemia and atherosclerosis. We have previously characterized Interleukin‐19 (IL‐19) as an anti‐inflammatory, Th2 cytokine. Past studies in our lab have determined that IL‐19 can decrease atherosclerosis in LDLr−/− mice and increase angiogenesis in the hind limb ischemia (HLI) model, suggesting that IL‐19 has both anti‐atherosclerotic and pro‐angiogenic effects.ObjectiveThe purpose of this study was to determine whether IL‐19 can induce angiogenesis within the background of hyperlipidemia and atherosclerosis and potentially reduce atherosclerosis and induce angiogenesis simultaneously.Methods and ResultsWe utilized three different, yet complementary platforms to test this hypothesis. We fed LDLr−/− mice high fat diet (HFD) for 12 weeks, then performed HLI surgery and continued HFD and treatment with rIL‐19 (10ng/g/day) or PBS intraperitoneal (IP) injections for an additional 4 weeks. Doppler imaging revealed increased perfusion in mice treated with IL‐19 when compared to PBS controls. Additional en face evaluation of the aortic arches of these mice demonstrated a trend toward decreased plaque burden in the IL‐19 treated mice, though it was not statistically significant. These data suggest that IL‐19 is capable of promoting angiogenesis, even in a hyperlipidemic environment. We used this same experimental model, but instead treated LDLr−/− mice with IL‐19 (10ng/g/day) or PBS by daily IP injection throughout the initial 12 weeks of HFD, in addition to four weeks following HLI surgery. Doppler imaging demonstrated increased perfusion in IL‐19 treated mice when compared to PBS controls, and en face evaluation showed decreased plaque burden in the IL‐19 treated mice, supporting our hypothesis that IL‐19 is capable of simultaneously decreasing atherosclerosis and promoting angiogenesis in the background of hyperlipidemia. Finally, we hypothesized that lack of IL‐19 would both reduce perfusion and exacerbate atherosclerosis. We generated a double knockout mouse model (dKO) by crossing the LDLr−/− with an IL‐19−/− mouse. We placed dKO and LDLr−/− mice on HFD for 12 weeks, completed HLI and performed Doppler imaging for 4 weeks. Preliminary results suggest dKO mice demonstrate both decreased perfusion and increased plaque burden.ConclusionsThe current dogma referred to as the Janus phenomenon suggests that pro‐angiogenic cytokines are also pro‐atherosclerotic. Collectively, these data suggest IL‐19 is the only cytokine to date that challenges this theory, demonstrating both pro‐angiogenic and anti‐atherosclerotic effects.Support or Funding InformationThis work was supported by grants HL115575 and HL117724 from the National Heart Lung, and Blood Institute of the National Institutes of Health, and Grant 13GRNT1685003 from the American Heart Association to MVA.

Analysis of interleukin 19 serum levels and single nucleotide polymorphisms in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease that affects multiple organs and diminishes a patients' quality of life. It has been suggested that interleukin 19 (IL-19) is engaged in intercellular signal transduction, which is related to the immune response and the local inflammatory reaction. Single nucleotide polymorphisms (SNPs) have been used to explore the genetic basis underlying the pathogenesis of SLE. In this study, we investigated the potential correlation between the functional IL19 SNP rs2243188 and SLE. The frequency of allele C in rs2243188 was lower in the SLE population, particularly when the dominant inheritance model was applied. There was also a significant difference in the allele C frequency between the lupus nephritis (LN) and non-LN groups in both the dominant and recessive inheritance models. In addition, we identified significant differences in the serum IL-19 levels between the different classes of SLE. Although this study is still at the preliminary stage, the correlations between the IL19 SNP and SLE, and between the IL-19 levels and the different subclasses of SLE provide a reference for further exploration.

Interleukin-19 and angiopoietin-2 can enhance angiogenesis of diabetic complications

This study was to investigate the role of interleukin-19 (IL-19) and angiopoietin-2 (Ang-2) in angiogenesis of type 2 diabetes (T2DM). In 240 patients with T2DM, IL-19 and Ang-2 levels were higher, IL-19 was positively correlated with Ang-2. IL-19 and Ang-2 might be involved in angiogenesis of T2DM complications.

Modulation of CD4+ and CD8+ T-Cell Function by Interleukin 19 and Interleukin 24 During Filarial Infections.

Interleukin 19 (IL-19) and interleukin 24 (IL-24) are cytokines that are highly expressed in filarial infections. To study the role of IL-19 and IL-24 in regulating T-cell responses, we examined the frequency of T-helper type 1 (Th1)/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, Th22/Tc22, and Tr1 cells in 26 filariae-infected individuals stimulated with filarial antigen following IL-19 or IL-24 neutralization. IL-19 or IL-24 neutralization resulted in significantly enhanced frequencies of Th1/Tc1 and/or Th17/Tc17 cells and significantly reduced frequencies of Th2/Tc2, Tr1, and/or Th9/Tc9 cells. Thus, we demonstrate that IL-19 and IL-24 are associated with the modulation of T-cell responses in filarial infections.

Abstract 579: Lack of Interleukin-19 Exacerbates Experimental Atherosclerosis

Interleukin-19 (IL-19) is a Th2 interleukin and a member of an IL-10 subfamily. Previous studies from our laboratory suggest an anti-inflammatory role for IL-19 outside the immune system, and for the vasculature in particular. Significantly more IL-19 is expressed in human atherosclerotic plaque from symptomatic rather than asymptomatic patients. However, addition of rIL-19 to LDLR-/- mice could significantly reduce atherosclerosis, suggesting that IL-19 expression is a compensatory, counter-regulatory mechanism. The purpose of this study was to test the hypothesis that absence of IL-19 results in increased atherosclerosis, and to characterize potential mechanisms for these effects. LDLR-/- mice were crossed with IL-19-/- mice, and homozygous double knock outs (DKO) were fed a high fat atherogenic diet for 14 weeks and compared with LDLR-/- mice. En face oil red O staining demonstrated that loss of IL-19 significantly exacerbated development of plaque in the aortic arch (13.41%+/-1.04 vs 21.13) +/-1.18, P<0.0001 for LDLR and DKO). Preliminary experiments were performed in which DKO were injected with 10ng/g/day rIL-19 or saline as control, and plaque quantitated en face staining. DKO mice rescued with rIL-19 had less plaque compared with saline controls (15.85+/-2.09% vs 22.43+/-2.80%, P=0.07). There was no significant difference in weight gain or serum cholesterol levels between these mice. As a first step to identify mechanisms, differences in cholesterol uptake in macrophage and VSMC were examined. Cholesterol uptake in BMDM from IL-19-/- mice were significantly decreased compared to wild-type controls (P<0.001). Conversely, cholesterol uptake in VSMC from IL-19-/- mice was significantly increased compared to wild-type (P<0.001). These data suggest that IL-19 plays an important part in development of atherosclerosis, with one potential mechanism being alterations in cholesterol homeostasis.

Interleukin-19 acts as a negative autocrine regulator of activated microglia.

Activated microglia can exert either neurotoxic or neuroprotective effects, and they play pivotal roles in the pathogenesis and progression of various neurological diseases. In this study, we used cDNA microarrays to show that interleukin-19 (IL-19), an IL-10 family cytokine, is markedly upregulated in activated microglia. Furthermore, we found that microglia are the only cells in the nervous system that express the IL-19 receptor, a heterodimer of the IL-20Rα and IL-20Rβ subunits. IL-19 deficiency increased the production of such pro-inflammatory cytokines as IL-6 and tumor necrosis factor-α in activated microglia, and IL-19 treatment suppressed this effect. Moreover, in a mouse model of Alzheimer’s disease, we observed upregulation of IL-19 in affected areas in association with disease progression. Our findings demonstrate that IL-19 is an anti-inflammatory cytokine, produced by activated microglia, that acts negatively on microglia in an autocrine manner. Thus, microglia may self-limit their inflammatory response by producing the negative regulator IL-19.

Interleukin-4 up-regulation of epidermal interleukin-19 expression in keratinocytes involves the binding of signal transducer and activator of transcription 6 (Stat6) to the imperfect Stat6 sites.

Interleukin-19 (IL-19) plays an important role in asthma by stimulating T helper type 2 (Th2) cytokine production. Interestingly, IL-4, a key Th2 cytokine, in turn up-regulates IL-19 expression in bronchial epithelial cells, so forming a positive feedback loop. In atopic dermatitis (AD), another Th2 disease closely related to asthma, IL-19 is up-regulated in the skin. We propose to use IL-4 transgenic (Tg) mice and human keratinocyte culture to delineate the molecular mechanisms involved in the up-regulation of IL-19 in AD. IL-19 is similarly up-regulated in the skin of IL-4 Tg mice as in human AD. Next we show that IL-4 up-regulates IL-19 expression in keratinocytes. Interestingly, the up-regulation was suppressed by a pan-Janus kinase (Jak) inhibitor, suggesting that the Jak-signal transducer and activator of transcription (Jak-STAT) pathway may be involved. Dominant negative studies further indicate that STAT6, but not other STATs, mediates the up-regulation. Serial 5' deletion of the IL-19 promoter and mutagenesis studies demonstrate that IL-4 up-regulation of IL-19 in keratinocytes involves two imperfect STAT6 response elements. Finally, chromatin immunoprecipitation assay studies indicate that IL-4 increases the binding of STAT6 to its response elements in the IL-19 promoter. Taken together, we delineate the detailed molecular pathway for IL-4 up-regulation of IL-19 in keratinocytes, which may play an important role in AD pathogenesis.

Association study of interleukin-19 rs2243188 polymorphism with systemic lupus erythematosus in a Chinese population

The purpose of this study was to evaluate whether a single-nucleotide polymorphism (SNP), rs2243188 of interleukin-19 (IL-19), show significant evidence for association with SLE in a Chinese population. A total of 545 SLE patients and 613 healthy controls were collected in the present study. The genotyping of IL-19 rs2243188 polymorphism was detected by TaqMan allele discrimination assay on the 7300 real time polymorphism chain reaction system. The minor C allele of rs2243188, relative to the major A allele, appeared to have a significantly lower frequency in SLE patients (31.0%) as compared with controls (35.5%) (χ2 = 5.19, p = 0.023). We also discovered a statistical significance in the dominant model (CC + CA versus AA: OR = 0.755, 95% CI = 0.598–0.953, p = 0.018). However, no significant difference in genotype distribution was found between SLE patients and controls (p = 0.056). Furthermore, an increased frequency of CC genotype were also detected in lupus nephritis (LN) groups as compared with non-LN groups (p = 0.024). Besides, the individuals with CC genotype had a 2.201-fold higher risk for the susceptibility to LN than those A allele carriers (AA + CA) (p = 0.006). Unfortunately, the analyses on the relationship of IL-19 rs2243188 with several clinical manifestations of SLE failed to find any significant results. In conclusion, our observations suggested the minor C allele of SNP rs2243188 might be a protective factor for SLE in a Chinese Han population. Moreover, the subgroup analysis highlighted that IL-19 rs2243188 SNP was associated with the susceptibility to LN patients.

Interleukin-19 Impairment in Active Crohn’s Disease Patients

The exact function of interleukin-19 (IL-19) on immune response is poorly understood. In mice, IL-19 up-regulates TNFα and IL-6 expression and its deficiency increases susceptibility to DSS-induced colitis. In humans, IL-19 favors a Th2 response and is elevated in several diseases. We here investigate the expression and effects of IL-19 on cells from active Crohn’s disease (CD) patient. Twenty-three active CD patients and 20 healthy controls (HC) were included. mRNA and protein IL-19 levels were analyzed in monocytes. IL-19 effects were determined in vitro on the T cell phenotype and in the production of cytokines by immune cells. We observed that unstimulated and TLR-activated monocytes expressed significantly lower IL-19 mRNA in active CD patients than in HC (logFC = −1.97 unstimulated; −1.88 with Pam3CSK4; and −1.91 with FSL-1; p<0.001). These results were confirmed at protein level. Exogenous IL-19 had an anti-inflammatory effect on HC but not on CD patients. IL-19 decreased TNFα production in PBMC (850.7±75.29 pg/ml vs 2626.0±350 pg/ml; p<0.01) and increased CTLA4 expression (22.04±1.55% vs 13.98±2.05%; p<0.05) and IL-4 production (32.5±8.9 pg/ml vs 13.5±2.9 pg/ml; p<0.05) in T cells from HC. IL-10 regulated IL-19 production in both active CD patients and HC. We observed that three of the miRNAs that can modulate IL-19 mRNA expression, were up-regulated in monocytes from active CD patients. These results suggested that IL-19 had an anti-inflammatory role in this study. Defects in IL-19 expression and the lack of response to this cytokine could contribute to inflammatory mechanisms in active CD patients.

Attenuation of Experimental Atherosclerosis by Interleukin-19

Interleukin-19 (IL-19) is a putative Th2, anti-inflammatory interleukin. Its expression and potential role in atherogenesis are unknown. IL-19 is not detected in normal artery and is expressed to a greater degree in plaque from symptomatic versus asymptomatic patients, suggesting a compensatory counter-regulatory function. We tested whether IL-19 could reduce atherosclerosis in susceptible mice and identified plausible mechanisms. LDLR(-/-) mice fed an atherogenic diet and injected with either 1.0 or 10.0 ng/g per day recombinant mouse IL-19 had significantly less plaque area in the aortic arch compared with controls (P<0.0001). Weight gain, cholesterol, and triglyceride levels were not significantly different. Gene expression in splenocytes from IL-19-treated mice demonstrated immune cell Th2 polarization, with decreased expression of T-bet, interferon-γ, interleukin-1β, and interleukin-12β and increased expression of GATA3 and FoxP3 mRNA. A greater percentage of lymphocytes were Th2 polarized in IL-19-treated mice. Cellular characterization of plaque by immunohistochemistry demonstrated that IL-19-treated mice have significantly less macrophage infiltrate compared with controls (P<0.001). Intravital microscopy revealed significantly less leukocyte adhesion in wild-type mice injected with IL-19 and fed an atherogenic diet compared with controls. Treatment of cultured endothelial cells, vascular smooth muscle cells, and bone marrow-derived macrophages with IL-19 resulted in a significant decrease in chemokine mRNA and mRNA stability protein human antigen R. These data suggest that IL-19 is a potent inhibitor of experimental atherosclerosis, with diverse mechanisms including immune cell polarization, decrease in macrophage adhesion, and decrease in gene expression. This may identify IL-19 as a novel therapeutic to limit vascular inflammation.

Signaling via the IL-20 receptor inhibits cutaneous production of IL-1β and IL-17A to promote infection with methicillin-resistant Staphylococcus aureus

Staphylococcus aureus causes the majority of human skin and soft tissue infections, and is a major infectious cause of mortality. Host defense mechanisms against S. aureus are incompletely understood. Interleukin (IL)-19, -20 and -24 signal through type I and type II IL-20 receptors and are associated with inflammatory skin diseases such as psoriasis and atopic dermatitis. We show here that these cytokines promote cutaneous S. aureus infection in mice by downregulating IL-1β- and IL-17A-dependent pathways. Similar effects of these cytokines were seen in human keratinocytes after S. aureus exposure, and antibody blockade of IL-20 receptor improved outcomes in infected mice. Our findings identify an immunosuppressive role for these cytokines during infection that could be therapeutically targeted to alter susceptibility to infection.

Interleukin-19 decreases leukocyte-endothelial cell interactions by reduction in endothelial cell adhesion molecule mRNA stability

Vascular endothelial cell (EC) inflammation is a key event in the pathogenesis of multiple vascular diseases. We tested the hypothesis that interleukin-19 (IL-19), an anti-inflammatory Th2 interleukin, could have a direct anti-inflammatory effect on ECs to decrease inflammation. IL-19 can significantly decrease tumor necrosis factor (TNF)-α-driven intracellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 mRNA and protein abundance in cultured human coronary artery ECs (P < 0.01). IL-19 treatment of ECs, but not monocytes, significantly reduced monocyte adhesion to EC monolayers (P < 0.01). In vivo, systemic administration of IL-19 could significantly reduce TNF-α-induced leukocyte rolling and adhesion in wild-type mice as assayed by intravital microscopy (P < 0.05). IL-19 does not reduce TNF-α-stimulated NF-κB activation in ECs but does decrease serine phosphorylation and cytoplasmic translocation of the mRNA stability factor HuR and significantly reduces stability of ICAM-1 and VCAM-1 mRNA (P < 0.01). These data are the first to report that IL-19 can reduce leukocyte-endothelial cell adhesion and the first to propose reduction in HuR-mediated mRNA stability of ICAM-1 and VCAM-1 as a mechanism. Expression of IL-19 by ECs may represent a protective mechanism to promote resolution of the vascular response to inflammation. Function of IL-19 outside of the immune system is a novel concept, suggesting that resident vascular cells can adopt a Th2 phenotype, and has important ramifications for numerous inflammatory diseases.

Attenuation of Experimental Atherosclerosis by Interleukin‐19

Interleukin‐19 (IL‐19) is a Th2, anti‐inflammatory interleukin. IL‐19 is expressed in several cell types in human atherosclerotic plaque. We tested the hypothesis that IL‐19 can reduce atherosclerotic plaque. LDLR−/− mice injected with either 1.0ng/g/day or 10.0ng/g/day rmIL‐19 had significantly less plaque area in the aortic arch compared with controls (p&lt;0.0001). Plaque regression studies indicated IL‐19 mice had significantly less plaque accumulation in the aortic arch compared with controls (p&lt;0.0001), but none compared to baseline controls. IL‐19 treated mice demonstrated immune cell Th2 polarization, with decreased T‐bet and IFNã, and increased expression of GATA3 and FoxP3 mRNA. Cellular characterization of plaque demonstrated IL‐19 treated mice have significantly less macrophage infiltrate compared with controls (p&lt;0.001). Intravital microscopy revealed significantly less leukocyte adhesion in wild‐type mice injected with IL‐19 and fed an atherogenic diet compared with controls. Treatment of cultured endothelial, vascular smooth muscle, and bone marrow‐derived macrophage with IL‐19 significantly decreased chemokine mRNA and the mRNA‐stability protein HuR. Together, these data indicate that IL‐19 is a potent inhibitor of experimental atherosclerosis, with diverse mechanisms including immune cell polarization, decrease in macrophage adhesion, and decrease in gene expression.

Abstract 79: Interleukin-19 Reduces Leukocyte-Endothelial Cell Interactions

Introduction Vascular endothelial cells (EC) actively participate in the pathogenesis of atherosclerosis by increasing expression of cell adhesion molecules which tether and adhere to leukocytes. The goal of the present study was to test the hypothesis that interleukin-19 (IL-19), an anti-inflammatory Th2 cytokine, can decrease expression of EC adhesion molecules and subsequently decrease leukocyte-endothelial cell interactions in vitro and in vivo. Methods and Results Cultured human coronary artery EC were pre-treated for various times with IL-19 (100 ng/ml) followed by stimulation with tumor necrosis factor-α (TNF-α; 10 ng/ml). IL-19 significantly reduced TNF-α-driven mRNA and protein abundance of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) (p&lt;0.01). Surprisingly, IL-19 did not inhibit TNF-α-activation of the transcription factor NFκB. ICAM-1 and VCAM-1 transcript stability was significantly reduced in IL-19-treated EC (p&lt;0.05). IL-19 treatment inhibited cytoplasmic localization of the mRNA stability factor HuR, and siRNA knock-down of HuR also decreased ICAM-1 and VCAM-1 transcript stability. IL-19 treatment of EC, but not treatment of monocytes, significantly reduced monocyte adhesion to EC monolayers (p&lt;0.01). Leukocyte rolling and adhesion was quantitated in C57/B6 mice treated with a single systemic dose of IL-19 (10 ng/g) followed by TNF-α (400 ng) using intravital microscopy. IL-19 treatment resulted in a significant decrease (p&lt;0.05) in TNF-α-driven leukocyte rolling and adhesion in vivo. Systemic administration of IL-19 (1.0ng/g/day) reduced CD68-positive cell infiltration into atherosclerotic plaque in LDLR -/- mice fed an atherogenic diet for 14 weeks (P&lt;0.01). Conclusion These data are the first report that IL-19 can reduce leukocyte-endothelial cell interactions in vitro and in vivo, and suggest a reduction in HuR-mediated mRNA stability of ICAM-1 and VCAM-1 as a mechanism. These results suggest that IL-19 is an important negative regulator of vascular inflammatory diseases.

Interleukin-19 (IL-19) Induces Heme Oxygenase-1 (HO-1) Expression and Decreases Reactive Oxygen Species in Human Vascular Smooth Muscle Cells

Heme oxygenase-1 (HO-1) has potent anti-inflammatory activity and recognized vascular protective effects. We have recently described the expression and vascular protective effects of an anti-inflammatory interleukin (IL-19), in vascular smooth muscle cells (VSMC) and injured arteries. The objective of this study was to link the anti-inflammatory effects of IL-19 with HO-1 expression in resident vascular cells. IL-19 induced HO-1 mRNA and protein in cultured human VSMC, as assayed by quantitative RT-PCR, immunoblot, and ELISA. IL-19 does not induce HO-1 mRNA or protein in human endothelial cells. IL-19 activates STAT3 in VSMC, and IL-19-induced HO-1 expression is significantly reduced by transfection of VSMC with STAT3 siRNA or mutation of the consensus STAT binding site in the HO-1 promoter. IL-19 treatment can significantly reduce ROS-induced apoptosis, as assayed by Annexin V flow cytometry. IL-19 significantly reduced ROS concentrations in cultured VSMC. The IL-19-induced reduction in ROS concentration is attenuated when HO-1 is reduced by siRNA, indicating that the IL-19-driven decrease in ROS is mediated by HO-1 expression. IL-19 reduces vascular ROS in vivo in mice treated with TNFα. This points to IL-19 as a potential therapeutic for vascular inflammatory diseases and a link for two previously unassociated protective processes: Th2 cytokine-induced anti-inflammation and ROS reduction.

Anti-Inflammatory Effects of Interleukin-19 in Vascular Disease

Despite aggressive dietary modification, lipid-lowering medications, and other interventional medical therapy, vascular disease continues to be a leading cause of mortality in the western world. It is a significant medical and socioeconomic problem contributing to mortality of multiple diseases including myocardial infarction, stroke, renal failure, and peripheral vascular disease. Morbidity and mortality of vascular disease are expected to worsen with the increasing number of patients with comorbid conditions such as obesity, metabolic syndrome, and diabetes mellitus type 2. Vascular diseases such as atherosclerosis, restenosis, and allograft vasculopathy are recognized to be driven by inflammation, and as such, cytokines which mediate inflammation not only represent important targets of rational therapy, but also can be considered as possible therapeutic modalities themselves. In this paper, we will examine the role of inflammatory cytokines and lymphocyte Th1/Th2 polarity in vascular inflammation, with a focus on atherosclerotic vascular disease. We will then introduce a recently described Th2 interleukin, interleukin-19 (IL-19), as a previously unrecognized mediator of vascular inflammatory disorders. We will review our current understanding of this interleukin in health and disease and present the possibility that IL-19 could represent a potential therapeutic to combat vascular inflammatory disease.

IL-19 as a Potential Therapeutic in Autoimmune and Inflammatory Diseases

Interleukin-19 (IL-19) is a member of the IL-10 family of cytokines. The last ten years from the finding of IL-19, investigations underline the role of IL-19 in the immunological diseases. It is known that expression of IL-19 is increased in the epidermis of patients with psoriasis, which is a Th1 dominant disease. Increased concentration of IL-19 has also been found in the serum of patients with asthma, which is a Th2 dominant disease. There is an increasing body of data demonstrating that IL-19 is associated with the pathogenesis of both Th1 and Th2 dominant diseases. Regarding the role of IL-19 on the innate immunity and inflammation, interestingly, in vitro studies have shown that lipopolysaccharide can stimulate human monocytes and macrophages to upregulate the expression of IL-19. IL- 19 is upregulated in macrophages after infection and lessens inflammation by suppressing the production of tumor necrosis factor-α , IL-6 and IL-12, but not by inducing IL-10. In addition, IL-19-deficient mice are susceptible to experimental colitis induced by dextran sodium sulfate, a disease which is characterized by excessive inflammatory responses of local macrophages and epithelial cells to intestinal microflora. In this review, we discuss our current understanding of the role of IL-19 in autoimmune and inflammatory diseases.

Interleukin-19: a new target to aim for?

Interleukin-19: a new target to aim for?

Anti-inflammatory cytokine interleukin-19 inhibits smooth muscle cell migration and activation of cytoskeletal regulators of VSMC motility

Vascular smooth muscle cell (VSMC) migration is an important cellular event in multiple vascular diseases, including atherosclerosis, restenosis, and transplant vasculopathy. Little is known regarding the effects of anti-inflammatory interleukins on VSMC migration. This study tested the hypothesis that an anti-inflammatory Th2 interleukin, interleukin-19 (IL-19), could decrease VSMC motility. IL-19 significantly decreased platelet-derived growth factor (PDGF)-stimulated VSMC chemotaxis in Boyden chambers and migration in scratch wound assays. IL-19 significantly decreased VSMC spreading in response to PDGF. To determine the molecular mechanism(s) for these cellular effects, we examined the effect of IL-19 on activation of proteins that regulate VSMC cytoskeletal dynamics and locomotion. IL-19 decreased PDGF-driven activation of several cytoskeletal regulatory proteins that play an important role in smooth muscle cell motility, including heat shock protein-27 (HSP27), myosin light chain (MLC), and cofilin. IL-19 decreased PDGF activation of the Rac1 and RhoA GTPases, important integrators of migratory signals. IL-19 was unable to inhibit VSMC migration nor was able to inhibit activation of cytoskeletal regulatory proteins in VSMC transduced with a constitutively active Rac1 mutant (RacV14), suggesting that IL-19 inhibits events proximal to Rac1 activation. Together, these data are the first to indicate that IL-19 can have important inhibitory effects on VSMC motility and activation of cytoskeletal regulatory proteins. This has important implications for the use of anti-inflammatory cytokines in the treatment of vascular occlusive disease.

Interleukin-19 Downregulates Interleukin-4-Induced Eotaxin Production in Human Nasal Fibroblasts

Interleukin-19 (IL-19), a member of the IL-10 family, is characterized as the cytokine suppressing the release and function of several proinflammatory cytokines. For regulation of local reaction in allergic rhinitis (AR), IL-19 might play an especially important role. We examined effects of IL-19 on IL-4-induced eotaxin production by human nasal fibroblasts. Early receptor-mediated events (expression of the suppressors of cytokine signaling (SOCS) and phosphorylation of signal transducer and activator of transcription 6 [STAT6]) by IL-19 was examined. Knockdown methods by RNAi were administered to investigate the involvement of those signal transductions. Pretreatment with IL-19 downregulates IL-4-induced eotaxin production, but not interferon-γ(IFN-γ)-induced RANTES. Pretreatment with IL-19 suppressed the IL-4-induced STAT6 phosphorylation. The IL-19 induced SOCS-1, but not SOCS-3 or SOCS-5. The SOCS-1 knockdown by RNAi diminished pretreatment with IL-19-induced down-regulation of eotaxin production. These results suggest that IL-19 down-regulates IL-4-induced eotaxin production via SOCS-1 in human nasal fibroblasts. In non-hematopoietic cells in AR, IL-19 might be an immunosuppressive factor.