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Man Chu, Lai Shan Tam, Jing Zhu, Delong Jiao, De Hua Liu, Zhe Cai, Jie Dong, Christopher Wei Kai Lam, Chun Kwok Wong
The newly named interleukin (IL)-36 subfamily member IL-38 has been shown to exert anti-inflammatory activity. However, the in vivo immunomodulatory activity of IL-38 was poorly investigated in systemic lupus erythematosus (SLE). We have investigated the expression of CD4(+)IL-17(+) Th17, CD4(+)IFN-γ(+) Th1 and CD3(+)CD4(-)CD8(-) double negative (DN) T cells and the related immunopathological mechanisms in female MRL/lpr mice model of spontaneous lupus-like disease, with or without IL-38 treatment. Intravenous administration of murine recombinant IL-38 into MRL/lpr mice can ameliorate the lupus-like clinical symptoms including proteinuria, leukocyteuria and skin lesions...
October 17, 2016: Immunobiology
Kelly M Cordoro, Derya Ucmak, Maria Hitraya-Low, Michael D Rosenblum, Wilson Liao
No abstract text is available yet for this article.
October 19, 2016: JAMA Dermatology
Amir S Yazdi, Kamran Ghoreschi
The interleukin-1 (IL-1) family consists of several pro- or anti-inflammatory proteins, with pro-inflammatory IL-1β being its best characterized member. IL-1β is one of the most prominent mediators of inflammation resulting in fever and immune activation via binding to IL-1 receptor 1. Due to its potency, its secretion is tightly regulated. First the transcription of the biologically inactive proform is induced by TLR activation, TNF, or IL-1 receptor activation by mature IL-1α or IL-1β. For the secretion of IL-1β, inflammasome activation as second stimulus is needed...
2016: Advances in Experimental Medicine and Biology
José Martin Murrieta-Coxca, Fernando Gómez-Chávez, Damariz Adriana Baeza-Martínez, Mario Eugenio Cancino-Diaz, Juan Carlos Cancino-Diaz, Sonia Mayra Pérez-Tapia, Elba Reyes-Maldonado, Sandra Rodríguez-Martínez
The IL-36 subfamily is a recently described group of cytokines with pro-inflammatory behavior, comprising three agonists (α, β, and γ), its receptor (R), and one antagonist (Ra). The expression and function of IL-36 subfamily members in the estrous cycle in healthy and infected pregnancy has not been described. We evaluated mRNA and protein expression of IL-36 family members during the estrous cycle, implantation, fetal development, and post-labor periods in a model of allogenic pregnancy in mice. We also explored the ability of Listeria monocytogenes to modulate the expression of IL-36 subfamily members during pregnancy...
2016: Frontiers in Immunology
Giorgos Bamias, Fabio Cominelli
PURPOSE OF REVIEW: Cytokines of the intestinal microenvironment largely dictate immunological responses after mucosal insults and the dominance of homeostatic or proinflammatory pathways. This review presents important recent studies on the role of specific cytokines in the pathogenesis of intestinal inflammation. RECENT FINDINGS: The particular mucosal effects of cytokines depend on their inherent properties but also the cellular origin, type of stimulatory antigens, intermolecular interactions, and the particular immunological milieu...
November 2016: Current Opinion in Gastroenterology
Charlie Bridgewood, Martin Stacey, Adewonuola Alase, Dimitris Lagos, Anne Graham, Miriam Wittmann
Interleukin-36 cytokines are predominantly expressed by epithelial cells. Significant upregulation of epidermal IL-36 is now a recognised characteristic of psoriatic skin inflammation. IL-36 is known to induce inflammatory responses in dendritic cells, fibroblasts and epithelial cells. Although vascular alterations are a hallmark of psoriatic lesions and dermal endothelial cells are well known to play a critical role in skin inflammation, the effects of IL-36 on endothelial cells are unexplored. We here show that endothelial cells including dermal microvascular cells express a functionally active IL-36 receptor...
September 27, 2016: Experimental Dermatology
Sol Kim, Drake W Williams, Cindy Lee, Terresa Kim, Atsushi Arai, Songtao Shi, Xinmin Li, Ki-Hyuk Shin, Mo K Kang, No-Hee Park, Reuben H Kim
Long-term administration of nitrogen-containing bisphosphonates can induce detrimental side effects such as bisphosphonate-related osteonecrosis of the jaw (BRONJ) in human. Although inflammation is known to be associated with BRONJ development, the detailed underlying mechanism remains unknown. Here, we report that the pro-inflammatory cytokine IL-36α is, in part, responsible for the BRONJ development. We found a notably higher level of IL-36α and lower level of collagen in the BRONJ lesions in mice. We also found that IL-36α remarkably suppressed TGF-β-mediated expression of Collα1 and α-Sma via the activation of Erk signaling pathway in mouse gingival mesenchymal stem cells...
August 27, 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Jennifer Palomo, Beatris Mastelic-Gavillet, Estelle Woldt, Sabina Troccaz, Emiliana Rodriguez, Gaby Palmer, Claire-Anne Siegrist, Cem Gabay
Human and mouse neonates exhibit limited vaccine responses characterized by predominant Th2 and limited Th1 responses. Because IL-36 exerts a synergic adjuvant effect with IL-12, enhancing Th1 polarization in adult (AD) mice, we administered IL-36β to neonatal (1-wk old) and AD control mice at the time of immunization with tetanus toxoid adsorbed to aluminum hydroxide (TT/Alum). Unexpectedly, the combination of IL-36β with TT/Alum, which was well tolerated in AD mice, proved toxic and even lethal in neonates...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Hyo Sang Song, Sang Jin Kim, Tae-In Park, Yong Hyun Jang, Eun-So Lee
BACKGROUND: Cutaneous pustular disorders include generalized pustular psoriasis (GPP) and acute generalized exanthematous pustulosis (AGEP). OBJECTIVE: To identify differences between GPP and AGEP, here we immunohistochemically evaluated interleukin (IL)-36 and the IL-23/Th17 axis. METHODS: This retrospective comparative immunohistochemical study was completed using 11 biopsies of 11 cases of GPP and 11 biopsies of 11 cases of AGEP. Through staining with the anti-IL-36-alpha (IL-36α), anti-IL-36 receptor antagonist (IL-36Ra), anti-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), anti-IL-23, anti-IL-17, and anti-IL-8 antibodies, main expression location and intensity were visualized in the epidermis and dermis...
August 2016: Annals of Dermatology
Laurence Feldmeyer, Kristine Heidemeyer, Nikhil Yawalkar
Acute generalized exanthematous pustulosis (AGEP) is a severe, usually drug-related reaction, characterized by an acute onset of mainly small non-follicular pustules on an erythematous base and spontaneous resolution usually within two weeks. Systemic involvement occurs in about 20% of cases. The course is mostly benign, and only in rare cases complications lead to life-threatening situations. Recent studies highlight the importance of genetic variations in interleukin-36 receptor antagonist gene (IL-36RN) in the pathogenesis of this disease...
2016: International Journal of Molecular Sciences
R S van Onkelen, M P Gosselink, M van Meurs, M J Melief, W R Schouten, J D Laman
BACKGROUND: Sphincter-preserving procedures for the treatment of transsphincteric fistulas fail in at least one out of every three patients. It has been suggested that failure is due to ongoing disease in the remaining fistula tract. Cytokines play an important role in inflammation. At present, biologicals targeting cytokines are available. Therefore, detection and identification of cytokines in anal fistulas might have implications for future treatment modalities. The objective of the present study was to assess local production of a selected panel of cytokines in anal fistulas, including pro-inflammatory interleukin (IL)-1β and tumor necrosis factor α (TNF-α)...
September 2016: Techniques in Coloproctology
Fadhil Ahsan, Pedro Moura-Alves, Ute Guhlich-Bornhof, Marion Klemm, Stefan H E Kaufmann, Jeroen Maertzdorf
Tuberculosis remains a major killer worldwide, not the least because of our incomplete knowledge of protective and pathogenic immune mechanism. The roles of the interleukin 1 (IL-1) and interleukin 18 pathways in host defense are well established, as are their regulation through the inflammasome complex. In contrast, the regulation of interleukin 36γ (IL-36γ), a recently described member of the IL-1 family, and its immunological relevance in host defense remain largely unknown. Here we show that Mycobacterium tuberculosis infection of macrophages induces IL-36γ production in a 2-stage-regulated fashion...
August 1, 2016: Journal of Infectious Diseases
Satveer K Mahil, Sophie Twelves, Katalin Farkas, Niovi Setta-Kaffetzi, A David Burden, Joanna E Gach, Alan D Irvine, László Képíró, Maja Mockenhaupt, Hazel H Oon, Jason Pinner, Annamari Ranki, Marieke Mb Seyger, Pere Soler-Palacin, Eoin R Storan, Eugene S Tan, Laurence Valeyrie-Allanore, Helen S Young, Richard C Trembath, Siew-Eng Choon, Marta Szell, Zsuzsanna Bata-Csorgo, Catherine H Smith, Paola Di Meglio, Jonathan N Barker, Francesca Capon
Prominent skin involvement is a defining characteristic of autoinflammatory disorders (AID) caused by abnormal IL-1 signalling. However, the pathways and cell types that drive cutaneous AID features remain poorly understood. We sought to address this issue by investigating the pathogenesis of pustular psoriasis, a model of AID with predominant cutaneous manifestations. We specifically characterised the impact of mutations affecting AP1S3, a disease gene previously identified by our group and validated here in a newly ascertained patient resource...
July 4, 2016: Journal of Investigative Dermatology
Sean M Winkle, Andrea L Throop, Melissa M Herbst-Kralovetz
IL-36γ is a proinflamatory cytokine which belongs to the IL-1 family of cytokines. It is expressed in the skin and by epithelial cells (ECs) lining lung and gut tissue. We used human 3-D organotypic cells, that recapitulate either in vivo human vaginal or cervical tissue, to explore the possible role of IL-36γ in host defense against pathogens in the human female reproductive tract (FRT). EC were exposed to compounds derived from virus or bacterial sources and induction and regulation of IL-36γ and its receptor was determined...
2016: Frontiers in Microbiology
Guanghui Yi, Joel A Ybe, Siddhartha S Saha, Gary Caviness, Ernest Raymond, Rajkumar Ganesan, M Lamine Mbow, C Cheng Kao
Signal transduction by the IL-36 receptor (IL-36R) is linked to several human diseases. However, the structure and function of the IL-36R is not well understood. A molecular model of the IL-36R complex was generated and a cell-based reporter assay was established to assess the signal transduction of recombinant subunits of the IL-36R. Mutational analyses and functional assays have identified residues of the receptor subunit IL-1Rrp2 needed for cytokine recognition, stable protein expression, disulfide bond formation and glycosylation that are critical for signal transduction...
August 5, 2016: Journal of Biological Chemistry
Rafael Penha, John Higgins, Shilla Mutamba, Paul Barrow, Yashwant Mahida, Neil Foster
We show that IL-36R is expressed by T (CD4+ and CD8+) and B (CD19+) lymphocytes in human blood and also by CD4+ T lymphocytes in the intestinal lamina propria. IL-36R protein was mostly stored in the cytoplasm of CD4 lymphocytes and B cells, during steady state conditions and the greatest expression of IL-36R mRNA was measured in CD4+ (T helper) lymphocytes. IL-36 β, which functions via IL-36R induced rapid and significant (P<0.05) proliferation of CD4+ lymphocytes, within 48h. IL-36R expression was also maintained on the surface of circulating CD4+ lymphocytes which enter the intestinal lamina propria...
September 2016: Cytokine
Damien Dietrich, Praxedis Martin, Vincent Flacher, Yu Sun, David Jarrossay, Nicolo Brembilla, Christopher Mueller, Heather A Arnett, Gaby Palmer, Jennifer Towne, Cem Gabay
Interleukin (IL)-36 cytokines belong to the IL-1 family and include three agonists, IL-36 α, β and γ and one inhibitor, IL-36 receptor antagonist (IL-36Ra). IL-36 and IL-1 (α and β) activate similar intracellular pathways via their related heterodimeric receptors, IL-36R/IL-1RAcP and IL-1R1/IL-1RAcP, respectively. However, excessive IL-36 versus IL-1 signaling induces different phenotypes in humans, which may be related to differential expression of their respective receptors. We examined the expression of IL-36R, IL-1R1 and IL-1RAcP mRNA in human peripheral blood, tonsil and skin immune cells by RT-qPCR...
August 2016: Cytokine
Danielle M Clancy, Conor M Henry, Pavel B Davidovich, Graeme P Sullivan, Ekaterina Belotcerkovskaya, Seamus J Martin
Recent evidence has strongly implicated IL-36 cytokines as key initiators of inflammation in the skin barrier. IL-36 cytokines belong to the extended IL-1 family and, similar to most members of this family, are expressed as inactive precursors that require proteolytic processing for activation. Because the proteases responsible for activation of members of the IL-36 subfamily have not been reported, we have developed a method for the production of biologically active IL-36 through introduction of a caspase cleavage motif, DEVD, within the N-termini of these cytokines...
April 2016: FEBS Open Bio
Marie Tauber, Elodie Bal, Xue-Yuan Pei, Marine Madrange, Amel Khelil, Houria Sahel, Akila Zenati, Mohamed Makrelouf, Khaled Boubridaa, Amel Chiali, Naima Smahi, Farida Otsmane, Bakar Bouajar, Slaheddine Marrakchi, Hamida Turki, Emmanuelle Bourrat, Manuelle Viguier, Yamina Hamel, Hervé Bachelez, Asma Smahi
Homozygous or compound heterozygous IL36RN gene mutations underlie the pathogenesis of psoriasis-related pustular eruptions including generalized pustular psoriasis, palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau, and acute generalized exanthematous pustular eruption. We identified two unreported IL36RN homozygous mutations (c.41C>A/p.Ser14X and c.420_426del/p.Gly141MetfsX29) in patients with familial generalized pustular psoriasis. We analyzed the impact of a spectrum of IL36RN mutations on IL-36 receptor antagonist protein by using site-directed mutagenesis and expression in HEK293T cells...
September 2016: Journal of Investigative Dermatology
Zhengrong Chen, Xin Zhao, Xinxing Zhang, Guangbo Zhang, Huiming Sun, Wujun Jiang, Yuqing Wang, Canhong Zhu, Wei Ji, Yongdong Yan
BACKGROUND: The purpose of this study is to explore the correlations of interleukin 36 (IL-36) and Soluble B7-H3 (sB7-H3) levels in bronchoalveolar lavage fluid (BALF) with clinical characteristics and laboratory findings. METHODS: A total of 35 children with M. pneumnoiae pneumonia (MPP) and 15 control subjects were enrolled. BALF concentrations of sB7-H3 and IL-36 were detected using enzyme-linked immunosorbent assays and clinical profiles of children with MPP were obtained...
2016: BMC Infectious Diseases
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