Preferential Binding to Elk-1 by SLE-Associated <i>IL10</i> Risk Allele Upregulates <i>IL10</i> Expression

Sakurai, Daisuke,Zhao, Jian,Deng, Yun,Kelly, Jennifer A.,Brown, Elizabeth E.,Harley, John B.,Bae, Sang-Cheol,Alarcό,n-Riquelme, Marta E.,Edberg, Jeffrey C.,Kimberly, Robert P.,Ramsey-Goldman, Ros Public Library of Science 2013 PLoS genetics Vol.9 No.10

<▼1><P>Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of <I>IL10</I> with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the <I>IL10</I> gene cluster including <I>IL19</I>, <I>IL20</I> and <I>IL24</I>, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported <I>IL10</I> variant, rs3024505 located at 1 kb downstream of <I>IL10</I>, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (<I>P</I> = 2.7×10<SUP>−8</SUP>, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of <I>IL10</I>, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of <I>IL10</I> mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating <I>IL10</I> expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the <I>IL10</I> rs3122605-G allele upregulates <I>IL10</I> expression and confers increased risk for SLE in European Americans.</P></▼1><▼2><P><B>Author Summary</B></P><P>Systemic lupus erythematosus (SLE), a debilitating autoimmune disease characterized by the production of pathogenic autoantibodies, has a strong genetic basis. Variants of the <I>IL10</I> gene, which encodes cytokine interleukin-10 (IL-10) with known function of promoting B cell hyperactivity and autoantibody production, are associated with SLE and other autoimmune diseases, and serum IL-10 levels are elevated in SLE patients correlating with increased disease activity. In this study, to discover SLE-predisposing causal variant(s), we assessed variants within the genomic region containing <I>IL10</I> and its gene family member <I>IL19</I>, <I>IL20</I> and <I>IL24</I> for association with SLE in case and control subjects from diverse ancestries. We identified SLE-associated SNP rs3122605 located at 9.2 kb upstream of <I>IL10</I> as the most likely causal variant in subjects of European ancestry. The SLE-risk allele of rs3122605 was dose-dependently associated with elevated <I>IL10</I> expression at both mRNA and protein levels in peripheral blood samples from SLE patients and controls, which could be explained, at least in part, by its preferential binding to Elk-1, a transcription factor activated in B cells during active disease of SLE patients. Elk-1-mediated IL-10 overexpression could be downregulated by inhibiting activation of mitogen-activated protein kinases, suggesting a potential therapeutic target for SLE.</P></▼2>

Chemotherapy and patient co-morbidity in ventral site hernia development

Mark A. Rettenmaier,Lisa N. Abaid,John V. Brown III,John P. Micha,Bram H. Goldstein 대한부인종양학회 2009 Journal of Gynecologic Oncology Vol.20 No.4

Objective: The risk factors associated with early ventral site hernia development following cancer surgery are ill defined and associated with an undetermined incidence. Methods: We analyzed 1,391 gynecologic cancer patient charts to identify the number of post-operative ventral site hernias over a nearly 6 year period. The following study variables were noted for evaluation: patient demographics, disease co-morbidity (hypertension, cardiovascular disease, diabetes), body mass index (BMI), treatment (e.g., chemotherapy regimen), intra-operative (e.g., bleeding) and postoperative (e.g., infection) complications, time to hernia development and length of hospital stay. Results: Twenty-six gynecologic cancer patients who developed a post-operative ventral hernia and subsequently underwent herniorrhaphy by our gynecologic oncology service were identified. The patient group’s overall time to initial hernia development was 11.23 months. Following a multiple regression analysis, we found that treatment (e.g., bevacizumab, liposomal doxorubicin or radiotherapy associated with compromised wound healing [p=0.0186] and disease co-morbidity [0.0432]) were significant prognostic indicators for an accelerated time to hernia development. Moreover, five patients underwent treatment associated with compromised wound healing and also had disease co-morbidity. In this sub-group, post-operative hernia development occurred more rapidly (3.8 months) than the overall group of patients. BMI and age did not impact time to hernia development (p>0.05). Conclusion: In the present gynecologic cancer patient series, a tendency for early post-operative hernia development appeared to coincide with treatment associated with compromised wound healing and disease co-morbidity. Gynecologic cancer surgeons should anticipate this potential complication and consider employing prophylactic intra-operative mesh to potentially prevent this condition. Objective: The risk factors associated with early ventral site hernia development following cancer surgery are ill defined and associated with an undetermined incidence. Methods: We analyzed 1,391 gynecologic cancer patient charts to identify the number of post-operative ventral site hernias over a nearly 6 year period. The following study variables were noted for evaluation: patient demographics, disease co-morbidity (hypertension, cardiovascular disease, diabetes), body mass index (BMI), treatment (e.g., chemotherapy regimen), intra-operative (e.g., bleeding) and postoperative (e.g., infection) complications, time to hernia development and length of hospital stay. Results: Twenty-six gynecologic cancer patients who developed a post-operative ventral hernia and subsequently underwent herniorrhaphy by our gynecologic oncology service were identified. The patient group’s overall time to initial hernia development was 11.23 months. Following a multiple regression analysis, we found that treatment (e.g., bevacizumab, liposomal doxorubicin or radiotherapy associated with compromised wound healing [p=0.0186] and disease co-morbidity [0.0432]) were significant prognostic indicators for an accelerated time to hernia development. Moreover, five patients underwent treatment associated with compromised wound healing and also had disease co-morbidity. In this sub-group, post-operative hernia development occurred more rapidly (3.8 months) than the overall group of patients. BMI and age did not impact time to hernia development (p>0.05). Conclusion: In the present gynecologic cancer patient series, a tendency for early post-operative hernia development appeared to coincide with treatment associated with compromised wound healing and disease co-morbidity. Gynecologic cancer surgeons should anticipate this potential complication and consider employing prophylactic intra-operative mesh to potentially prevent this condition.

Multi-cultural nature of the Uniting Church and its mission

John P. Brown 장로회신학대학교 세계선교연구원 2012 선교와 신학 Vol.29 No.-

한국선교 어제, 오늘 그리고 내일 - 선교의 관계성 : 복음과 선교와 교회의 일치

John P. Brown 장로회신학대학교 세계선교연구원 2001 선교와 신학 Vol.8 No.-

보고 들으시는 하나님에 대한 증거

John P. Brown 장로회신학대학교 세계선교연구원 2002 선교와 신학 Vol.9 No.-

Witnesses to the God Who hears and Sees

John P. Brown 장로회신학대학교 세계선교연구원 2002 선교와 신학 Vol.9 No.-

Rethinking Mission : New Direction For A New Century

John P. Brown 장로회신학대학교 세계선교연구원 2001 선교와 신학 Vol.8 No.-

Korean Mission Yesterday, Today & Tomorrow - RElationships in Mission

John P. Brown 장로회신학대학교 세계선교연구원 2001 선교와 신학 Vol.8 No.-

Transcriptional activation of hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis through VEGF and S100A8

Ahn, G-One,Seita, Jun,Hong, Beom-Ju,Kim, Young-Eun,Bok, Seoyeon,Lee, Chan-Ju,Kim, Kwang Soon,Lee, Jerry C.,Leeper, Nicholas J.,Cooke, John P.,Kim, Hak Jae,Kim, Il Han,Weissman, Irving L.,Brown, J. Mar National Academy of Sciences 2014 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.111 No.7

<P>Emerging evidence indicates that myeloid cells are essential for promoting new blood vessel formation by secreting various angiogenic factors. Given that hypoxia-inducible factor (HIF) is a critical regulator for angiogenesis, we questioned whether HIF in myeloid cells also plays a role in promoting angiogenesis. To address this question, we generated a unique strain of myeloid-specific knockout mice targeting HIF pathways using human S100A8 as a myeloid-specific promoter. We observed that mutant mice where HIF-1 is transcriptionally activated in myeloid cells (by deletion of the von Hippel–Lindau gene) resulted in erythema, enhanced neovascularization in matrigel plugs, and increased production of vascular endothelial growth factor (VEGF) in the bone marrow, all of which were completely abrogated by either genetic or pharmacological inactivation of HIF-1. We further found that monocytes were the major effector producing VEGF and S100A8 proteins driving neovascularization in matrigel. Moreover, by using a mouse model of hindlimb ischemia we observed significantly improved blood flow in mice intramuscularly injected with HIF-1–activated monocytes. This study therefore demonstrates that HIF-1 activation in myeloid cells promotes angiogenesis through VEGF and S100A8 and that this may become an attractive therapeutic strategy to treat diseases with vascular defects.</P>

Plant U13 orthologues and orphan snoRNAs identified by RNomics of RNA from Arabidopsis nucleoli

Kim, Sang Hyon,Spensley, Mark,Choi, Seung Kook,Calixto, Cristiane P. G.,Pendle, Ali F.,Koroleva, Olga,Shaw, Peter J.,Brown, John W. S. Oxford University Press 2010 Nucleic acids research Vol.38 No.9

<P>Small nucleolar RNAs (snoRNAs) and small Cajal body-specific RNAs (scaRNAs) are non-coding RNAs whose main function in eukaryotes is to guide the modification of nucleotides in ribosomal and spliceosomal small nuclear RNAs, respectively. Full-length sequences of Arabidopsis snoRNAs and scaRNAs have been obtained from cDNA libraries of capped and uncapped small RNAs using RNA from isolated nucleoli from Arabidopsis cell cultures. We have identified 31 novel snoRNA genes (9 box C/D and 22 box H/ACA) and 15 new variants of previously described snoRNAs. Three related capped snoRNAs with a distinct gene organization and structure were identified as orthologues of animal U13snoRNAs. In addition, eight of the novel genes had no complementarity to rRNAs or snRNAs and are therefore putative orphan snoRNAs potentially reflecting wider functions for these RNAs. The nucleolar localization of a number of the snoRNAs and the localization to nuclear bodies of two putative scaRNAs was confirmed by <I>in situ</I> hybridization. The majority of the novel snoRNA genes were found in new gene clusters or as part of previously described clusters. These results expand the repertoire of Arabidopsis snoRNAs to 188 snoRNA genes with 294 gene variants.</P>