Interleukin-17 and Interleukin-22 Induced Proinflammatory Cytokine Production in Keratinocytes via Inhibitor of Nuclear FactorκB Kinase-α Expression

( Kyung Ah Cho ),( Jin Young Kim ),( So Youn Woo ),( Hyun Jeong Park ),( Kyung Ho Lee ),( Chi Un Pae ) 대한피부과학회 2012 Annals of Dermatology Vol.24 No.4

Background: The pathogenesis of psoriasis may involve the interleukin (IL)-23 and Th17-mediated immune responses. Th17 cells secret IL-17 and IL-22, which mediates dermal inflammation and acanthosis. Objective: As inhibitor of nuclear factor κB kinase-α (IKKα) has been previously identified as a primary regulator of keratinocyte differentiation and proliferation, we proposed that IL-17 and IL-22 might affect keratinocyte differentiation by changing the expression of IKKα. Methods: We employed HaCaT cells maintained culture medium at a low calcium concentration (0.06 mM) and induced differentiation by switching to the high concentration (2.8 mM) media with IL-17 or IL-22, then compared the IKKα expression and the cell cycle. We employed reconstituted human epidermal skin (Neoderm) and mice ears for the in vivo studies. Results: Elevated calcium concentration induced IKKα expression and terminal differentiation with cell cycle arrest in HaCaT cell cultures. Moreover, IL-17 and IL-22 treatment also induced IKKα in HaCaT cells and reconstituted human epidermis. IKKα induction was also noted, following the injection of IL-17 and IL-22 into mice ears. Conclusion: Although the induction of IKKα was accompanied by keratinocyte diffe-rentiation, IL-17 and IL-22 did not affect calcium-mediated differentiation or the cell cycle. Rather, IL-17 and IL-22 appear to contribute to the inflammation occurring via the induction of IKKα from keratinocytes or skin layers. (Ann Dermatol 24(4) 398∼405, 2012)

Interleukin-22 Attenuates Acute Pancreatitis-Associated Intestinal Mucosa Injury in Mice via STAT3 Activation

( Jinxia Bai ),( Jinyun Bai ),( Meng Yang ) 대한소화기기능성질환·운동학회 2021 Gut and Liver Vol.15 No.5

Background/Aims: Interleukin-22 (IL-22) is an important cytokine maintaining homeostasis at barrier surfaces. In this study, the role of IL-22 in acute pancreatitis-associated intestinal injury was further explored. Methods: Severe acute pancreatitis (SAP) was induced by administration of L-arginine in Balb/c mice at different time gradients. Histopathological examinations were made in both the pancreas and small intestine. Furthermore, recombinant murine IL-22 (rIL-22) was administrated to L-arginine-induced SAP mice by intraperitoneal injection. The mRNA levels of IL-22R1, Reg-IIIβ, Reg-IIIγ, Bcl-2, and Bcl-xL were detected in the small intestine by real-time polymerase chain reaction, and protein levels of total and phosphorylated STAT3 were assessed via Western blot. Results: Compared with normal control group, 72 hours of L-arginine exposure induced the most characteristic histopathological changes of SAP, evidenced by pathological changes and serum amylase levels. Meanwhile, significant pancreatitis-associated intestinal mucosa injury was also observed. The gene expression levels of antimicrobial proteins Reg-IIIβ, Reg-IIIγ and anti-apoptosis proteins Bcl-2, Bcl-xL were downregulated in small intestine. Furthermore, Larginine- induced SAP was attenuated by rIL-22 treatment. Importantly, pancreatitis-associated intestinal mucosa injury was also ameliorated, reflected by improved pathological changes and significant increase in gene expression levels of Reg-IIIβ, Reg-IIIγ, Bcl-2 and Bcl-xL. Consistently, serum amylase levels and mortality were decreased in mice treated with rIL-22. Mechanistically, the upregulated expressions of these protective genes were achieved by activating STAT3. Conclusions: Exogenous rIL-22 attenuates L-arginine-induced acute pancreatitis and intestinal mucosa injury in mice, via activating STAT3 signaling pathway and enhancing the expression of antimicrobial peptides and antiapoptotic genes. (Gut Liver 2021;15:771-781)

Amelioration of DSS-Induced Acute Colitis in Mice by Recombinant Monomeric Human Interleukin-22

Kim Suhyun,Hong Eun-Hye,Lee Cheol-Ki,Ryu Yiseul,Jeong Hyunjin,Heo Seungnyeong,이중재,고현정 대한면역학회 2022 Immune Network Vol.22 No.3

IL-22, a pleiotropic cytokine, is known to have a profound effect on the regeneration of damaged intestinal barriers. The tissue-protective properties of IL-22 are expected to be potentially exploited in the attenuation and treatment of colitis. However, because of the disease-promoting role of IL-22 in chronic inflammation, a comprehensive evaluation is required to translate IL-22 into the clinical domain. Here, we present the effective production of soluble human IL-22 in bacteria to prove whether recombinant IL-22 has the ability to ameliorate colitis and inflammation. IL-22 was expressed in the form of a biologically active monomer and non-functional oligomers. Monomeric IL-22 (mIL-22) was highly purified through a series of 3 separate chromatographic methods and an enzymatic reaction. We reveal that the resulting mIL-22 is correctly folded and is able to phosphorylate STAT3 in HT-29 cells. Subsequently, we demonstrate that mIL-22 enables the attenuation of dextran sodium sulfate-induced acute colitis in mice, as well as the suppression of pro-inflammatory cytokine production. Collectively, our results suggest that the recombinant mIL-22 is suitable to study the biological roles of endogenous IL-22 in immune responses and can be developed as a biological agent associated with inflammatory disorders.

Distribution of Interleukin-22–secreting Immune Cells in Conjunctival Associated Lymphoid Tissue

윤창호,이대승,정현정,류진석,김미금 대한안과학회 2018 Korean Journal of Ophthalmology Vol.32 No.2

Interleukin (IL)-22 is a cytokine involved in epithelial cell regeneration. Currently, no research studieshave analyzed the distribution of the three distinct IL-22–secreting cell populations in human or mouse conjunctiva. This study investigated the distribution of the three main populations of IL-22–secreting immune cells, αβ Thcells, γδ T cells, or innate cells (innate lymphoid cells [ILCs] or natural killer cells), in conjunctival associated lymphoidtissues (CALTs) in human and mouse models. Methods: We collected discarded cadaveric bulbar conjunctival tissue specimens after preservation of the corneo-limbal tissue for keratoplasty from four enucleated eyes of the domestic donor. The bulbar conjunctivatissue, including the cornea from normal (n = 27) or abraded (n = 4) B6 mice, were excised and pooled in RPMI1640 media. After the lymphoid cells were gated in forward and side scattering, the αβ Th cells, γδ T cells, orinnate lymphoid cells were positively or negatively gated using anti-CD3, anti-γδ TCR, and anti–IL-22 antibodies,with a FACSCanto flow cytometer. Results: In normal human conjunctiva, the percentage and number of cells were highest in αβ Th cells, followed byγδ T cells and CD3– γδ TCR – IL-22+ innate cells (presumed ILCs, pILCs) (Kruskal-Wallis test, p = 0.012). In normalmice keratoconjunctiva, the percentage and total number were highest in γδ T cells, followed by αβ Th cellsand pILCs (Kruskal-Wallis test, p = 0.0004); in corneal abraded mice, the population of αβ Th cells and pILCstended to increase. Conclusions: This study suggests that three distinctive populations of IL-22–secreting immune cells are presentin CALTs of both humans and mice, and the proportions of IL-22+αβ Th cells, γδ T cells, and pILCs in CALTs inhumans might be differently distributed from those in normal mice.

From intestinal dysbiosis to alcohol-associated liver disease

Beatriz Garcia Mendes,Bernd Schnabl 대한간학회 2020 Clinical and Molecular Hepatology(대한간학회지) Vol.26 No.4

Alcohol-associated intestinal dysbiosis and bacterial overgrowth can lead to a dysregulation of tryptophan metabolism and lower production of indoles. Several of these indole derivatives are aryl hydrocarbon receptor ligands that, in turn, are involved in antimicrobial defense via induction of interleukin-22 (IL-22). IL-22 increases the expression of intestinal regenerating islet-derived 3 (Reg3) lectins, which maintain low bacterial colonization of the inner mucus layer and reduce bacterial translocation to the liver. Chronic alcohol consumption is associated with reduced intestinal expression of Reg3β and Reg3γ, increased numbers of mucosa-associated bacteria and bacterial translocation. Translocated microbial products and viable bacteria reach the liver and activate the innate immune system. Release of inflammatory molecules promotes inflammation, contributes to hepatocyte death and results in a fibrotic response. This review summarizes the mechanisms by which chronic alcohol intake changes the gut microbiota and contributes to alcohol-associated liver disease by changing microbial-derived metabolites.

The Slough of Cicadidae Periostracum Ameliorated Lichenification by Inhibiting Interleukin (IL)-22/Janus Kinase (JAK) 1/Signal Transducer and Activator of Transcription (STAT) 3 Pathway in Atopic Dermatitis

박강혜,권남규,김미혜,양웅모 한국축산식품학회 2023 한국축산식품학회지 Vol.43 No.5

It is known that animal-origin medicine could be one of effective treatment to remedy atopic dermatitis (AD) by controlling the cytokines. Cicadidae Periostracum (CP), the slough of Cryptotympana pustulata, has been frequently used for treating AD and skin affliction in traditional Korean Medicine. This study is aimed at investigating the ameliorating effects of CP on AD and its potential mechanism. The dinitrochlorobenzene sensitized mice were treated with CP for 2 weeks. The various biomarkers and the dermatitis scores presented that CP treatment can induce the visual and biological improvements of AD model. Pruritus, the most serious symptom of AD, which can cause repeated scratching behaviors and finally lead to lichenification, was reduced with CP treatment by regulating the inflammatory reactions. In addition, CP treatment diminished the number of mast cells that are known for causing inflammatory reactions. Moreover, it is proven that CP can decline secretion of interleukin-22, which means CP treatment has anti-inflammatory effects. CP treatment can correct the imbalance of helper T (Th)1 and Th2, downregulating thymic stromal lymphopoietin that leads to decrease of mRNA level of inflammatory cytokines. The crucial role of CP treatment is controlling of the Janus kinase 1/signal transducer and activator of transcription 3 pathway. In addition, CP treatment has the inhibitory effects on kallikrein related peptidase (KLK) 5 and KLK7. Taken together, CP treatment can ameliorate most symptoms and problems caused by AD disease, improving the AD patients’ life quality.

Interleukin-22 are expressed earlier than IL-17A during Riemerella anatipestifer infection in ducks

Paula Leona T. Cammayo,Rochelle A. Flores,Cherry P. Fernandez-Colorado,Fahmida Afrin,Binh T. Nguyen,Woo H. Kim,Wongi Min 한국가금학회 2020 한국가금학회 정기총회 및 학술발표회 Vol.2020 No.11

Enhanced Type 2 Immune Reactions by Increased IL-22/IL-22Ra1 Signaling in Chronic Rhinosinusitis With Nasal Polyps

김동규,Ara Jo,Hee-Suk Lim,김진엽,Kyoung Mi Eun,Jayoung Oh,Joon Kon Kim,Seong-Ho Cho,김대우 대한천식알레르기학회 2020 Allergy, Asthma & Immunology Research Vol.12 No.6

Purpose: Recent studies have revealed the pathogenic role of interleukin (IL)-22 in atopic dermatitis and asthma. However, little is known about the role of IL-22 in the pathophysiology of chronic rhinosinusitis with nasal polyps. We aimed to investigate the expression of IL-22 and its pathogenic function in type 2 immune reactions of nasal polyps (NP). Methods: Protein levels of inflammatory mediators were determined by multiplex immunoassay, and principal component analysis (PCA) was performed. Immunofluorescence analysis and mast cell culture were used to determine the cellular sources of IL-22. Normal human bronchial epithelial (NHBE) cells were stimulated using IL-22 in combination with diverse cytokines, and thymic stromal lymphopoietin (TSLP) was measured. Results: IL-22 expression was not up-regulated in NP compared with control tissues, but IL-22-high NP revealed distinct features characterized by type 2 inflammatory cytokines such as chemokine (C-C motif) ligand (CCL)-11, CCL-24, and IL-5 on the PCA. Additionally, IL-22 positively correlated with type 2 immune mediators and the disease severity in NP. For the localization of the cellular sources of IL-22 in eosinophilic NP, it was expressed in cells mostly composed of eosinophil peroxidase-positive cells and partially of tryptase-positive cells. The human mast cell line, LAD2 cells, released IL-22 mediated by immunoglobulin E. Moreover, IL-22 receptor subunit alpha-1 (IL-22Ra1) expression was significantly increased in NP. IL-22Ra1 was up-regulated with poly(I:C) stimulation in NHBE cells. Furthermore, TSLP production was enhanced when stimulated with a combination of IL-13, poly(I:C), and IL-22. Treatment with anti-IL-22Ra1 also inhibited IL-22-induced enhancement of TSLP production. Conclusion: IL-22 was associated with type 2 inflammatory reactions in NP. The IL-22/IL-22Ra1 axis was enhanced and might be involved in type 2 inflammatory reactions via TSLP production in NP.

Expanded IL-22+ Group 3 Innate Lymphoid Cells and Role of Oxidized LDL-C in the Pathogenesis of Axial Spondyloarthritis with Dyslipidaemia

Min Hong Ki,Moon Jeonghyeon,Lee Seon-Yeong,Lee A Ram,Lee Chae Rim,Lee Jennifer,곽승기,조미라,박성환 대한면역학회 2021 Immune Network Vol.21 No.6

Group 3 innate lymphoid cells (ILC3), which express IL-22 and IL-17A, has been introduced as one of pathologic cells in axial spondyloarthritis (axSpA). Dyslipidaemia should be managed in axSpA patients to reduce cardiovascular disease, and dyslipidaemia promotes inflammation. This study aimed to reveal the role of circulating ILC3 in axSpA and the impact of dyslipidaemia on axSpA pathogenesis. AxSpA patients with or without dyslipidaemia and healthy control were recruited. Peripheral blood samples were collected, and flow cytometry analysis of circulating ILC3 and CD4+ T cells was performed. The correlation between Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-reactive protein (CRP) and circulating immune cells was evaluated. The effect of oxidized low-density lipoprotein cholesterol (oxLDL-C) on immune cell differentiation was confirmed. AxSpA human monocytes were cultured with with oxLDL-C, IL-22, or oxLDL-C plus IL-22 to evaluate osteoclastogenesis using tartrate-resistant acid phosphatase (TRAP) staining and real-time quantitative PCR of osteoclast-related gene expression. Total of 34 axSpA patients (13 with dyslipidaemia and 21 without) were included in the analysis. Circulating IL-22+ ILC3 and Th17 were significantly elevated in axSpA patients with dyslipidaemia (p=0.001 and p=0.034, respectively), and circulating IL-22+ ILC3 significantly correlated with ASDAS-CRP (Rho=0.4198 and p=0.0367). Stimulation with oxLDL-C significantly increased IL-22+ ILC3, NKp44− ILC3, and Th17 cells, and these were reversed by CD36 blocking agent. IL-22 and oxLDL-C increased TRAP+ cells and osteoclast-related gene expression. This study suggested potential role of circulating IL-22+ ILC3 as biomarker in axSpA. Furthermore, dyslipidaemia augmented IL-22+ ILC3 differentiation, and oxLDL-C and IL-22 markedly increased osteoclastogenesis of axSpA.

Dang-Gui-Liu-Huang Tang a traditional herbal formula, ameliorates imiquimod-induced psoriasis-like skin inflammation in mice by inhibiting IL-22 production

Nguyen, Ly Thi Huong,Ahn, Sang-Hyun,Nguyen, Uy Thai,Yang, In-Jun Elsevier 2018 Phytomedicine Vol.47 No.-

<P><B>Abstract</B></P> <P><B>Background</B></P> <P>The traditional herbal formula, Dang-Gui-Liu-Huang Tang (DGLHT) has been previously shown to inhibit T lymphocyte proliferation and suppress dendritic cell function. Hypothesis/Purpose: To assess the therapeutic value of DGLHT for the treatment of psoriasis, a Th1 and/or Th17 cell-mediated inflammatory skin disease, and to investigate the underlying molecular mechanisms.</P> <P><B>Methods</B></P> <P>An <I>in vivo</I> mouse model of imiquimod (IMQ)-induced psoriasis-like inflammation was used to investigate the effect of DGLHT. The anti-inflammatory effects of an ethanolic extract of DGLHT (DGLHT-E) and the mechanism responsible were examined in an <I>in vitro</I> model using IL-1α, IL-17A, IL-22, oncostatin M, plus TNF-α (M5) stimulated HaCaT cells. The anti-proliferative effect of DGLHT-E was examined by analyzing the expression levels of K16, K17 and Ki67 in IL-22 stimulated HaCaT cells. <I>Results:</I> Topical application of 1% DGLHT-E significantly reduced psoriasis-like symptoms including scaling and epidermal hyperplasia in IMQ-treated mice. Immunohistochemical studies showed that DGLHT-E exerted potent anti-inflammatory effects by inhibiting IL-22 production in local skin lesions. DGLHT-E also attenuated the productions of CXCL10 and CCL20 in M5-stimulated HaCaT cells by suppressing the ERK1/2, JNK and STAT3 signaling pathways. Furthermore, berberine hydrochloride, a primary constituent of DGLHT-E inhibited the expressions of the proliferation markers K16 and K17 in IL-22 stimulated HaCaT cells.</P> <P><B>Conclusion</B></P> <P>These results suggested that DGLHT-E offers a possible treatment for psoriasis, and that berberine hydrochloride might be a useful component of ointment-based treatments for psoriatic lesions.</P> <P><B>Graphical <B>abstract</B> </B></P> <P>[DISPLAY OMISSION]</P>