Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism

被引:495
作者
Schauber, Jurgen
Dorschner, Robert A.
Coda, Alvin B.
Buchau, Amanda S.
Liu, Philip T.
Kiken, David
Helfrich, Yolanda R.
Kang, Sewon
Elalieh, Hashem Z.
Steinmeyer, Andreas
Zuegel, Ulrich
Bikle, Daniel D.
Modlin, Robert L.
Gallo, Richard L.
机构
[1] Univ Calif San Diego, Div Dermatol, San Diego, CA 92103 USA
[2] VA San Diego Healthcare Syst, San Diego, CA USA
[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Dermatol, Los Angeles, CA USA
[4] Univ Michigan, Dept Dermatol, Ann Arbor, MI 48109 USA
[5] Univ Calif San Francisco, Vet Affairs Med Ctr, Endocrine Unit, Dept Med, San Francisco, CA 94143 USA
[6] Schering AG, Med Chem, D-1000 Berlin, Germany
[7] Schering AG, Corp Res Business Area Inflammat, D-1000 Berlin, Germany
关键词
D O I
10.1172/JCI30142
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
An essential element of the innate immune response to injury is the capacity to recognize microbial invasion and stimulate production of antimicrobial peptides. We investigated how this process is controlled in the epidermis. Keratinocytes surrounding a wound increased expression of the genes coding for the microbial pattern recognition receptors CD14 and TLR2, complementing an increase in cathelicidin antimicrobial peptide expression. These genes were induced by 1,25(OH)(2) vitamin D-3 (1,25D3; its active form), suggesting a role for vitamin D-3 in this process. How 1,25D3 could participate in the injury response was explained by findings that the levels of CYP27B1, which converts 250H vitamin D3 (25133) to active 1,25D3, were increased in wounds and induced in keratinocytes in response to TGF-beta(1). Blocking the vitamin D receptor, inhibiting CYP27B1, or limiting 25D3 availability prevented TGF-beta(1), from inducing cathelicidin, CD14, or TLR2 in human keratinocytes, while CYP27B1-deficient mice failed to increase CD14 expression following wounding. The functional consequence of these observations was confirmed by demonstrating that 1,25D3 enabled keratinocytes to recognize microbial components through TLR2 and respond by cathelicidin production. Thus, we demonstrate what we believe to be a previously unexpected role for vitamin D-3 in innate immunity, enabling keratinocytes to recognize and respond to microbes and to protect wounds against infection.
引用
收藏
页码:803 / 811
页数:9
相关论文
共 39 条
[1]   Pathogen recognition and innate immunity [J].
Akira, S ;
Uematsu, S ;
Takeuchi, O .
CELL, 2006, 124 (04) :783-801
[2]   TRANSPLEURAL GRADIENT OF 1,25-DIHYDROXYVITAMIN-D IN TUBERCULOUS PLEURITIS [J].
BARNES, PF ;
MODLIN, RL ;
BIKLE, DD ;
ADAMS, JS .
JOURNAL OF CLINICAL INVESTIGATION, 1989, 83 (05) :1527-1532
[3]   TUMOR-NECROSIS-FACTOR-ALPHA REGULATION OF 1,25-DIHYDROXYVITAMIN-D PRODUCTION BY HUMAN KERATINOCYTES [J].
BIKLE, DD ;
PILLAI, S ;
GEE, E ;
HINCENBERGS, M .
ENDOCRINOLOGY, 1991, 129 (01) :33-38
[4]   Calcium and 1,25(OH)2D:: interacting drivers of epidermal differentiation [J].
Bikle, DD ;
Oda, Y ;
Xie, Z .
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 2004, 89-90 (1-5) :355-360
[5]   Mice lacking 250HD 1α-hydroxylase demonstrate decreased epidermal differentiation and barrier function [J].
Bikle, DD ;
Chang, S ;
Crumine, D ;
Elalieh, H ;
Man, MQ ;
Dardenne, O ;
Xie, Z ;
St Arnaud, R ;
Feingold, K ;
Elias, PM .
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 2004, 89-90 (1-5) :347-353
[6]   REGULATION OF 1,25-DIHYDROXYVITAMIN-D PRODUCTION IN HUMAN KERATINOCYTES BY INTERFERON-GAMMA [J].
BIKLE, DD ;
PILLAI, S ;
GEE, E ;
HINCENBERGS, M .
ENDOCRINOLOGY, 1989, 124 (02) :655-660
[7]   Cutaneous defense mechanisms by antimicrobial peptides [J].
Braff, MH ;
Bardan, A ;
Nizet, V ;
Gallo, RL .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2005, 125 (01) :9-13
[8]   Keratinocyte production of cathelicidin provides direct activity against bacterial skin pathogens [J].
Braff, MH ;
Zaiou, M ;
Fierer, J ;
Nizet, V ;
Gallo, RL .
INFECTION AND IMMUNITY, 2005, 73 (10) :6771-6781
[9]   Vitamin D [J].
Brown, AJ ;
Dusso, A ;
Slatopolsky, E .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 1999, 277 (02) :F157-F175
[10]   The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection [J].
Chromek, Milan ;
Slamova, Zuzana ;
Bergman, Peter ;
Kovacs, Laszlo ;
Podracka, L'udmila ;
Ehren, Ingrid ;
Hokfelt, Tomas ;
Gudmundsson, Gudmundur H. ;
Gallo, Richard L. ;
Agerberth, Birgitta ;
Brauner, Annelie .
NATURE MEDICINE, 2006, 12 (06) :636-641