Exaptation of an ancient Alu short interspersed element provides a highly conserved vitamin D-mediated innate immune response in humans and primates
© Gombart et al; licensee BioMed Central Ltd. 2009
Received: 12 March 2009
Accepted: 16 July 2009
Published: 16 July 2009
About 45% of the human genome is comprised of mobile transposable elements or "junk DNA". The exaptation or co-option of these elements to provide important cellular functions is hypothesized to have played a powerful force in evolution; however, proven examples are rare. An ancient primate-specific Alu short interspersed element (SINE) put the human CAMP gene under the regulation of the vitamin D pathway by providing a perfect vitamin D receptor binding element (VDRE) in its promoter. Subsequent studies demonstrated that the vitamin D-cathelicidin pathway may be a key component of a novel innate immune response of human to infection. The lack of evolutionary conservation in non-primate mammals suggested that this is a primate-specific adaptation. Evidence for evolutionary conservation of this regulation in additional primate lineages would provide strong evidence that the TLR2/1-vitamin D-cathelicidin pathway evolved as a biologically important immune response mechanism protecting human and non-human primates against infection.
PCR-based amplification of the Alu SINE from human and non-human primate genomic DNA and subsequent sequence analysis, revealed perfect structural conservation of the VDRE in all primates examined. Reporter gene studies and induction of the endogenous CAMP gene in Rhesus macaque peripheral blood mononuclear cells demonstrated that the VDREs were conserved functionally. In addition, New World monkeys (NWMs) have maintained additional, functional steroid-hormone receptor binding sites in the AluSx SINE that confer retinoic acid responsiveness and provide potential thyroid hormone receptor binding sites. These sites were less well-conserved during human, ape and Old World monkey (OWM) evolution and the human CAMP gene does not respond to either retinoic acid or thyroid hormone.
We demonstrated that the VDRE in the CAMP gene originated from the exaptation of an AluSx SINE in the lineage leading to humans, apes, OWMs and NWMs and remained under purifying selection for the last 55–60 million years. We present convincing evidence of an evolutionarily fixed, Alu-mediated divergence in steroid hormone nuclear receptor gene regulation between humans/primates and other mammals. Evolutionary selection to place the primate CAMP gene under regulation of the vitamin D pathway potentiates the innate immune response and may counter the anti-inflammatory properties of vitamin D.
The pioneering work of Britten and colleagues showed that eukaryotic genomes contain significant amounts of repetitive DNA [1, 2]. They theorized that repetitive DNA might provide binding sites for transcriptional factors, thus influencing gene expression patterns . Furthermore, it was postulated that the movement of repetitive sequences in the genome could generate a source of evolutionary variation for gene expression . The human genome project has revealed that 44% of the human genome is comprised of mobile transposable elements . Changes in regulation of gene expression by these elements may play an important role in the evolution of human and primate-specific responses to infectious disease.
The primate-specific Alu family of mobile, middle repetitive short-interspersed elements (SINEs) constitutes about 10% of the human genome [6, 7]. They have an increased concentration of transcription factor binding sites and examples of their potential to control gene transcription both positively and negatively have been described [8–11]. We recently identified the insertion of an AluSx SINE in the promoter of the human cathelicidin antimicrobial peptide (CAMP) gene that provides an essential cis-element that may be crucial for an effective innate immune response in humans . The element provides a perfect consensus sequence for binding by the vitamin D receptor (VDR) and confers vitamin D-responsiveness to the CAMP gene in a number of tissues and cell types [12–16]. Prior studies using both deletional and site-directed mutagenesis of the VDRE located in the AluSx of the human CAMP promoter demonstrated that it is sufficient and essential for induction of the CAMP gene by VDR [12–14, 16]. Furthermore, chromatin immunoprecipitation showed binding of the VDR to this site .
In vitro studies demonstrated that activation of the vitamin D pathway by the Mycobacterium tuberculosis (Mtb) 19-kDa lipoprotein via TLR2/1 leads to induction of CAMP and a potential innate immune response against Mtb infection [17, 18]. Furthermore, injury to the skin induces TGFβ-mediated activation of the vitamin D pathway, induction of CAMP and activation of TLR2 and CD14 expression . This enables keratinocytes to recognize pathogens and protect the wound from infection . Taken together, these studies argue that the vitamin D-cathelicidin pathway is a key component of a novel innate immune response to infection.
We demonstrated that regulation of the CAMP gene by VDR and its ligand 1,25(OH)2 vitamin D3 is not evolutionarily conserved in mice, rats or dogs because the promoters of their genes lack a VDRE . The AluSx SINE containing the VDRE was present in the promoters of both chimps and humans suggesting that this immune response is a primate-specific adaptation . Evidence for the evolutionary conservation of this regulation in additional primate lineages would provide strong evidence that the TLR2/1-vitamin D-cathelicidin pathway evolved as a biologically important immune response mechanism for protecting human and non-human primates against infection.
We hypothesized that the AluSx containing the VDRE would be evolutionarily conserved in humans, apes, Old World monkeys (OWMs) and New World monkeys (NWMs). To test this, we analyzed the sequence and function of the Alu SINEs amplified from genomic DNA of five apes, three OWMs and four NWMs. We determined that the VDRE is conserved in all three groups of primates and lacking in prosimians. Also, we discovered that NWMs may have maintained additional, functional steroid-hormone receptor binding sites in the AluSx SINE that could confer retinoic acid (RA) and thyroid hormone (TH) responsiveness; however, these sites were less highly conserved during human, ape and OWM evolution.
Comparisons of genomes ranging from ancient fish to modern humans have provided circumstantial evidence that the exaptation  or co-option of TEs to serve important cellular functions has been a powerful force in evolution [21, 22]; however, proven examples are rare. Our study provides strong evidence that exaptation of an AluSx SINE provides a novel, biologically important innate immune response via the vitamin D-pathway that is evolutionarily conserved in humans and non-human primates, but absent in other mammals.
Alu sequences are present in the CAMP promoters of Old and New World Monkeys
The VDRE is located in the 3'-half of the Alu-element. Alignment with the AluSx consensus sequence indicates the VDRE was formed by the duplication of the sequence 5'-CGGGTTCAA-3' (Fig. 1C). This resulted in the positioning of two direct repeats of 5'-GGTTCA-3' separated by a 3-nucleotide spacer and is an ideal VDRE .
A search of the trace archive data base at NCBI using the human CAMP coding region, identified overlapping sequences that included the 5'-promoter region of the Otolemur garnetti (a prosimian) CAMP gene (data not shown). Sequence alignments showed that the Alu-element and VDRE found in the other primates was absent in the O. garnetti (Figure 1C). This indicates that prosimians lack an Alu with a VDRE in their CAMP promoters.
Functional conservation of VDRE activity
Induction of the CAMP gene by 1,25(OH)2D3 in R. mulatta mononuclear cells
To determine if the endogenous CAMP gene could be induced by 1,25(OH)2D3 in cells from a non-human primate, we isolated mononuclear cells (MNCs) from the peripheral blood of two individual M. mulatta and treated these cells with either vehicle (ethanol) or 100 nM 1,25(OH)2D3 for 48 h. Analysis by QRT-PCR showed that the CAMP gene was induced 6.8- and 12.2-fold. These results demonstrate that it is possible to induce the endogenous CAMP gene in non-human primates with 1,25(OH)2D3 (Figure 2C). Also, we detected the protein, CAP18, encoded by the CAMP gene in the plasma of the two M. mulatta (189 and 253 ng/ml) indicating that the protein is secreted into the blood as reported for humans .
Other potential steroid hormone receptor response elements in the Alu-element are not functional
An AluSx SINE resides within the first 500 bp of the human MPO gene promoter . The first DR2 was unable to bind RAR, but the second potential DR2 bound RAR and was responsive to retinoic acid . Also, the DR4 was responsive to thyroid hormone . Alignment of our primate sequences against the AluSx consensus sequence revealed that two nucleotide positions in the third direct repeat were changed from G-to-A and C-to-A for all hominids and Old World monkeys, but were unchanged in all the New World monkeys (Figure 3). These changes potentially could impair binding of either the RAR or TR and prevent activation of the CAMP gene by retinoic acid or thyroid hormone. These changes were not present in the third direct repeat of the MPO AluSx which is responsive to both steroid hormones .
NWM CAMP gene responds to retinoic acid
NWMs are resistant to vitamin D, sex steroids and glucocortocoids [30, 31]. They are characterized by high circulating levels of these hormones. Interestingly, NWMs do not appear to have resistance to RA or T3 .
The third direct repeat in the NWM Alu-elements is identical to that in the consensus AluSx sequence (Figure 3). Furthermore, the fourth direct repeat acquired a G to A change in the sixth nucleotide of the direct repeat (Figure 3) and would be predicted to make the second DR2 a better binding site for RAR as it is identical to the site in the MPO gene that responds to RA . Furthermore, the changes would make the DR4 a better binding site for the TR and is identical to the MPO DR4 that responds to TR .
Early in primate evolution (about 60 million years ago), the major groups of Hominidae (humans and other apes), OWMs, NWMs and prosimians (lemurs and lorises) evolved independently and the origin and amplification of Alu elements was concomitant with this primate radiation . Examples of Alu elements implicated in gene regulation have been identified [9–11, 21, 22, 26, 33–36]. Identification of convincing examples of evolutionarily-fixed, novel regulatory patterns requires evidence of: 1) a known transposable element (TE) sequence in the region of the gene; 2) the TE sequence affecting regulation of the nearby gene; 3) the gene having some function and 4) the TE having been present long enough to be fixed [10, 34]. For some of the above examples, it was demonstrated that the Alu elements are conserved in humans, apes and/or OWMs, but was not examined in NWMs; therefore, the last requirement was only partially addressed .
Previously, we and others established the first three criteria for the CAMP gene [12, 13]. Here we provide convincing evidence for the last requirement. We demonstrate that the TE (AluSx SINE) acquired a VDRE through a duplication event and has undergone approximately 60 million years of purifying selection during the primate radiation to become fixed in the genomes of present-day humans, apes, OWMs and NWMs (Figure 1). The distribution of this Alu in the different lineages is consistent with current primate phylogeny and the ancient age of this class of Alu . Furthermore, we have shown that, as with humans, the non-human, primate VDREs are functional both in vitro and in vivo (Figure 2). Regulation of the CAMP gene by vitamin D as conferred by the AluSx in its promoter meets each of the above criteria. This study demonstrates that exaptation of vitamin D-mediated gene regulation by an AluSx SINE provided a novel, biologically-important innate immune response that is conserved in humans and non-human primates, but not other mammalian species. It is a convincing example of an evolutionarily-fixed, Alu-mediated divergence in steroid hormone nuclear receptor gene regulation between humans/primates and other mammals.
During the course of evolution, each group of primates has acquired differences in the ability to respond to steroid hormones . Surprisingly, NWM have circulating 1,25(OH)2D3 levels that are up to two orders of magnitude higher than those observed in OWM, apes and humans [30, 38]. The NWMs are naturally resistant to 1,25(OH)2D3 due to the over expression of VDRE-binding proteins (VDRE-BP) that requires NWMs to maintain high levels of 1,25(OH)2D3 to displace it from binding sites [39, 40]. Also, NWM are resistant to estrogen, testosterone and glucocortocoids [31, 38], but remain sensitive to retinoic acid and thyroid hormone . Although these differences in vitamin D physiology exist, we have demonstrated that the VDRE is conserved in all three groups of primates. Subclasses of AluS sequences provide a significant source of potential hormone response elements for retinoic acid and thyroid hormone receptors [36, 41]. Interestingly, in NWMs these elements are well conserved in the CAMP promoter Alu and have acquired additional changes that make them potentially better binding sites for RAR and TR (Figures 3 and 5). On the other hand, these sites were altered during hominid, ape and OWM evolution and did not respond to RA or TH (Figures 3 and 4). Retaining responses to both vitamin D and these other steroid hormones may be necessary for a proper innate immune response in vitamin D-resistant, but RA- and TH-sensitive NWMs. The importance of these binding sites to the expression of the CAMP gene remains to be fully elucidated.
The importance of vitamin D and the active metabolite 1,25(OH)2D3 in immune function became apparent with the discovery of VDR expression in activated inflammatory cells [42, 43]. Also, it was demonstrated that 1,25(OH)2D3 was produced by activated macrophages [44, 45] and 1,25(OH)2D3 inhibited T-cell activation and proliferation [46–49]. Subsequently, it was shown that vitamin D has an inhibitory action on the adaptive immune system with a shift from Th1 to Th2 and T regulatory cells and inhibition of Th17 development [50–54]. Suppression of the adaptive system and the anti-inflammatory effects of vitamin D are probably beneficial for conditions that involve autoimmunity ; however, it could prove detrimental for some infections [56, 57].
The human CAMP gene is not induced consistently by pro-inflammatory stimuli [12, 16, 58–61]. Additionally, infection of macrophages with Mtb and other cell types with pathogens leads to the repression of the CAMP gene [18, 62, 63]. Acquisition of the VDRE by ancestral primates that likely possessed high levels of vitamin D like today's non-human primates  would have provided a pathway for induction of the CAMP gene in cells such as macrophages or epithelial barrier cells that are capable of activating the vitamin D pathway in response to infection or wounding [17, 19]. The activation of the vitamin D pathway provides a way for human macrophages to prevent the suppression of the CAMP gene when activated with TLR2 or TLR4 ligands . Thus, induction of the CAMP gene by 1,25(OH)2D3 provides a possible mechanism for primates to counteract pathogen-mediated suppression and modulate the immune response.
We have demonstrated that the VDRE in the CAMP gene originated from the exaptation of an AluSx SINE in the lineage leading to humans, apes, OWMs and NWMs. It has remained under purifying selection for the last 55–60 million years. It is a convincing example of an evolutionarily fixed, Alu-mediated divergence in steroid hormone nuclear receptor gene regulation between humans/primates and other mammals.
The host immune response to serious infections is a delicate balancing act as bacterial clearance by an exuberant immune system often leads to self-induced immune damage, whereas a feeble immune response enables bacteria to persist and cause pathogen-induced diseases. We propose a possible model that explains how the vitamin D3 pathway may combat infection while minimizing damage to the host by its immune system. 1) TLR-activation by a pathogen activates production of 1,25(OH)2D3 and induction of VDR expression in monocytes . 2) VDR-signaling increases production of hCAP18/LL-37 protein (encoded by the CAMP gene) to kill the pathogen [17, 66]; 3) this subsequently downregulates TLR in the monocytes  and 4) nuclear translocation of NF-κB/RelA is blocked, thus muting the response to LPS and the production of inflammatory cytokines [67–71]. Finally, hCAP18/LL-37 secreted by monocytes , binds circulating LPS and dampens the signal to innate immune cells as well as directly acting on the TLR-to-NF-kappaB pathway in monocytes/macrophages . Evolutionary selection to place the CAMP gene under regulation of the vitamin D pathway may enable suppression of inflammation while potentiating innate immunity, thus maximizing the overall immune response to a pathogen and minimizing damage to the host.
Human and non-human primate genomic DNA samples
The human genomic DNA was provided by Dr. Carl Miller (Cedars-Sinai Medical Center, Los Angeles, CA). The M. mulatta, C. jacchus and A. trivirgatus genomic DNAs were provided by Dr. John Adams (University of California Los Angeles, Los Angeles, CA). The genomic DNA for C. aethiops was isolated from the COS-1 cell line. The remaining non-human primate genomic DNAs were purchased (Corriel Institute for Medical Research, Camden, NJ).
PCR amplification, sequencing and cloning
The Alu sequences in the primate CAMP promoters were amplified using the following primers: Forward, 5'-gggcaacttgtcccttgcaaga-3' and Reverse, 5'-gggtgctcaagagcgttaaatccc-3'. The primers were located outside the Alu SINE in regions that showed the highest homology among human, chimp, mouse, rat and canine sequences. The primer sequences were identical to the human and chimp promoters.
PCR was performed with 100 ng of genomic DNA in 50 μl reactions with HotMaster Taq polymerase (Eppendorf AG, Hamburg, Germany). The primers were used at a final concentration of 300 nM. The annealing temperature was 50°C and 35 cycles of PCR were performed. The PCR products were purified from the reaction using a DNA Clean and Concentrator-5 spin column (Zymo Research, Orange, CA). The PCR products were sequenced using the PCR primers described above and the Big DyeTM Terminator v.3 cycle sequencing as instructed by the manufacturer (Applied Biosystems, Inc., Foster City, CA). The sequences were analyzed and aligned using the Bioedit Sequence Alignment Editor software (Tom Hall, Ibis Biosciences, Carlsbad, CA). The PCR products for the human, M. mulatta and C. aethiops Alu-elements were cloned into the pCR-2.1 Topo-TA vector (Invitrogen, Carlsbad, CA). These fragments were subcloned into pGL4.20 [Luc2/Puro] (Promega Corporation, Madison, WI).
The U937, HL-60, NB4 and B95-8 cells were grown in RPMI 1640 supplemented with 10% FBS and antibiotics. Cells were treated with either 1,25(OH)2D3 (1 or 100 nM), 500 nM all trans retinoic acid (ATRA) or thyroid hormone (T3, 10 or 100 nM) for 24 h. Whole blood from M. mulatta (two different animals) was obtained from the California National Primate Research Center (University of California, Davis, CA). The mononuclear cells (MNC) were isolated on a Ficoll gradient after lysis of the red blood cells. The MNC were cultured in RPMI 1640 with 10% FBS and antibiotics in the presence of either vehicle (95% ethanol) or 1,25(OH)2D3 (100 nM) for 48 h.
Reporter Assays, RNA isolation and QRT-PCR
U937 cells were co-transfected with empty vector (pGL4.20) or vector containing the Alu SINE (1 μg) and phTKRL (0.1 μg) using Effectene reagent as described by the manufacturer (Qiagen, Chatsworth, CA). Cells were lysed and dual-luciferase assays performed as instructed by the manufacturer (Promgea Corporation).
Total RNA was isolated using Trizol Reagent according to the manufacturer (Invitrogen). The synthesis of the cDNA and QRT-PCR for the human CAMP gene and 18S rRNA were performed as described previously . The expression of ITGAM (CDllb) and MPO were analyzed by QRT-PCR using SYBR-green as described previously [12, 73].
AFG is a Principal Investigator in the Linus Pauling Institute and Associate Professor in the Department of Biochemistry and Biophysics at Oregon State University, 2011 ALS Bldg, Corvallis, OR 97331-7305. E-mail: email@example.com
TS is a postdoctoral researcher in the Linus Pauling Institute and Department of Biochemistry and Biophysics at Oregon State University, 2011 ALS Bldg, Corvallis, OR 97331-7305. E-mail: firstname.lastname@example.org
HPK is a Professor of Medicine at the David Geffen School of Medicine at UCLA, Director, Division of Hematology/Oncology at Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048. E-mail: email@example.com
We are very grateful to Niels Borregaard (University of Copenhagen) and Charlotte Horn (University of Copenhagen) for measuring CAP18 levels in the primate plasma samples. We thank John Adams (University of California Los Angeles) and Carl Miller (Cedars-Sinai Medical Center) for providing reagents. We thank Jinchuan Xing (University of Utah) for discussions on Alu SINEs and Michael Selsted (University of California Irvine) for advice on obtaining primate plasma samples. We thank Niels Borregaard, Martin Hewison (University of California Los Angeles) and Mary Fantacone (Oregon State University) for critically reading the manuscript. This research was supported by NIH grant 5R01AI065604-04 (AFG) and the Sheryl Wiessberg Lymphoma Foundation (HPK) and the Parker Hughes Fund (HPK).
- Waring M, Britten RJ: Nucleotide sequence repetition: a rapidly reassociating fraction of mouse DNA. Science. 1966, 154 (750): 791-794. 10.1126/science.154.3750.791.View ArticlePubMedGoogle Scholar
- Britten RJ, Kohne DE: Repeated sequences in DNA. Hundreds of thousands of copies of DNA sequences have been incorporated into the genomes of higher organisms. Science. 1968, 161 (841): 529-540. 10.1126/science.161.3841.529.View ArticlePubMedGoogle Scholar
- Britten RJ, Davidson EH: Gene regulation for higher cells: a theory. Science. 1969, 165 (891): 349-357. 10.1126/science.165.3891.349.View ArticlePubMedGoogle Scholar
- Britten RJ, Davidson EH: Repetitive and non-repetitive DNA sequences and a speculation on the origins of evolutionary novelty. Q Rev Biol. 1971, 46 (2): 111-138. 10.1086/406830.View ArticlePubMedGoogle Scholar
- Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, et al: Initial sequencing and analysis of the human genome. Nature. 2001, 409 (6822): 860-921. 10.1038/35057062.View ArticlePubMedGoogle Scholar
- Kramerov DA, Vassetzky NS: Short retroposons in eukaryotic genomes. Int Rev Cytol. 2005, 247: 165-221. 10.1016/S0074-7696(05)47004-7.View ArticlePubMedGoogle Scholar
- Batzer MA, Deininger PL: Alu repeats and human genomic diversity. Nat Rev Genet. 2002, 3 (5): 370-379. 10.1038/nrg798.View ArticlePubMedGoogle Scholar
- Thornburg BG, Gotea V, Makalowski W: Transposable elements as a significant source of transcription regulating signals. Gene. 2006, 365: 104-110. 10.1016/j.gene.2005.09.036.View ArticlePubMedGoogle Scholar
- Brosius J: RNAs from all categories generate retrosequences that may be exapted as novel genes or regulatory elements. Gene. 1999, 238 (1): 115-134. 10.1016/S0378-1119(99)00227-9.View ArticlePubMedGoogle Scholar
- Britten RJ: DNA sequence insertion and evolutionary variation in gene regulation. Proc Natl Acad Sci USA. 1996, 93 (18): 9374-9377. 10.1073/pnas.93.18.9374.PubMed CentralView ArticlePubMedGoogle Scholar
- Britten RJ: Mobile elements inserted in the distant past have taken on important functions. Gene. 1997, 205 (1–2): 177-182. 10.1016/S0378-1119(97)00399-5.View ArticlePubMedGoogle Scholar
- Gombart AF, Borregaard N, Koeffler HP: Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 2005, 19 (9): 1067-1077. 10.1096/fj.04-3284com.View ArticlePubMedGoogle Scholar
- Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, Tavera-Mendoza L, Lin R, Hanrahan JW, Mader S, et al: Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol. 2004, 173 (5): 2909-2912.View ArticlePubMedGoogle Scholar
- Weber G, Heilborn JD, Chamorro Jimenez CI, Hammarsjo A, Torma H, Stahle M: Vitamin D induces the antimicrobial protein hCAP18 in human skin. J Invest Dermatol. 2005, 124 (5): 1080-1082. 10.1111/j.0022-202X.2005.23687.x.View ArticlePubMedGoogle Scholar
- Gombart AF, O'Kelly J, Saito T, Koeffler HP: Regulation of the CAMP gene by 1,25(OH)2D3 in various tissues. J Steroid Biochem Mol Biol. 2007, 103 (3–5): 552-557. 10.1016/j.jsbmb.2006.12.095.View ArticlePubMedGoogle Scholar
- Schauber J, Dorschner RA, Yamasaki K, Brouha B, Gallo RL: Control of the innate epithelial antimicrobial response is cell-type specific and dependent on relevant microenvironmental stimuli. Immunology. 2006, 118 (4): 509-519.PubMed CentralPubMedGoogle Scholar
- Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, et al: Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006, 311 (5768): 1770-1773. 10.1126/science.1123933.View ArticlePubMedGoogle Scholar
- Martineau AR, Wilkinson KA, Newton SM, Floto RA, Norman AW, Skolimowska K, Davidson RN, Sorensen OE, Kampmann B, Griffiths CJ, et al: IFN-gamma- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin LL-37. J Immunol. 2007, 178 (11): 7190-7198.View ArticlePubMedGoogle Scholar
- Schauber J, Dorschner RA, Coda AB, Buchau AS, Liu PT, Kiken D, Helfrich YR, Kang S, Elalieh HZ, Steinmeyer A, et al: Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest. 2007, 117 (3): 803-811. 10.1172/JCI30142.PubMed CentralView ArticlePubMedGoogle Scholar
- Gould SJ, Vrba ES: Exaptation; a missing term in the science of form. Paleobiology. 1982, 8 (1): 4-15.Google Scholar
- Feschotte C: Transposable elements and the evolution of regulatory networks. Nat Rev Genet. 2008, 9 (5): 397-405. 10.1038/nrg2337.PubMed CentralView ArticlePubMedGoogle Scholar
- Bejerano G, Lowe CB, Ahituv N, King B, Siepel A, Salama SR, Rubin EM, Kent WJ, Haussler D: A distal enhancer and an ultraconserved exon are derived from a novel retroposon. Nature. 2006, 441 (7089): 87-90. 10.1038/nature04696.View ArticlePubMedGoogle Scholar
- Naar AM, Boutin JM, Lipkin SM, Yu VC, Holloway JM, Glass CK, Rosenfeld MG: The orientation and spacing of core DNA-binding motifs dictate selective transcriptional responses to three nuclear receptors. Cell. 1991, 65 (7): 1267-1279. 10.1016/0092-8674(91)90021-P.View ArticlePubMedGoogle Scholar
- Sorensen O, Cowland JB, Askaa J, Borregaard N: An ELISA for hCAP-18, the cathelicidin present in human neutrophils and plasma. J Immunol Methods. 1997, 206 (1–2): 53-59. 10.1016/S0022-1759(97)00084-7.View ArticlePubMedGoogle Scholar
- Vansant G, Reynolds WF: The consensus sequence of a major Alu subfamily contains a functional retinoic acid response element. Proc Natl Acad Sci USA. 1995, 92 (18): 8229-8233. 10.1073/pnas.92.18.8229.PubMed CentralView ArticlePubMedGoogle Scholar
- Piedrafita FJ, Molander RB, Vansant G, Orlova EA, Pfahl M, Reynolds WF: An Alu element in the myeloperoxidase promoter contains a composite SP1-thyroid hormone-retinoic acid response element. J Biol Chem. 1996, 271 (24): 14412-14420. 10.1074/jbc.271.24.14412.View ArticlePubMedGoogle Scholar
- Norris J, Fan D, Aleman C, Marks JR, Futreal PA, Wiseman RW, Iglehart JD, Deininger PL, McDonnell DP: Identification of a new subclass of Alu DNA repeats which can function as estrogen receptor-dependent transcriptional enhancers. J Biol Chem. 1995, 270 (39): 22777-22782. 10.1074/jbc.270.39.22777.View ArticlePubMedGoogle Scholar
- Marchetti M, Falanga A, Giovanelli S, Oldani E, Barbui T: All-trans-retinoic acid increases adhesion to endothelium of the human promyelocytic leukaemia cell line NB4. Br J Haematol. 1996, 93 (2): 360-366. 10.1046/j.1365-2141.1996.4911029.x.View ArticlePubMedGoogle Scholar
- Koeffler HP, Ranyard J, Pertcheck M: Myeloperoxidase: its structure and expression during myeloid differentiation. Blood. 1985, 65 (2): 484-491.PubMedGoogle Scholar
- Adams JS, Gacad MA, Baker AJ, Kheun G, Rude RK: Diminished internalization and action of 1,25-dihydroxyvitamin D3 in dermal fibroblasts cultured from New World primates. Endocrinology. 1985, 116 (6): 2523-2527.View ArticlePubMedGoogle Scholar
- Brandon DD, Markwick AJ, Chrousos GP, Loriaux DL: Glucocorticoid Resistance in Humans and Nonhuman Primates. Cancer Res. 1989, 49 (8_Supplement): 2203s-2213.PubMedGoogle Scholar
- Arbelle MAG Jonathan, Spencer Carole, Adams John: Absence of thyroid hormone resistance in vitamin D-;resistant new world primates. American Journal of Primatology. 1994, 32 (3): 215-222. 10.1002/ajp.1350320308.View ArticleGoogle Scholar
- Trujillo MA, Sakagashira M, Eberhardt NL: The human growth hormone gene contains a silencer embedded within an Alu repeat in the 3'-flanking region. Mol Endocrinol. 2006, 20 (10): 2559-2575. 10.1210/me.2006-0147.View ArticlePubMedGoogle Scholar
- Britten RJ: Cases of ancient mobile element DNA insertions that now affect gene regulation. Mol Phylogenet Evol. 1996, 5 (1): 13-17. 10.1006/mpev.1996.0003.View ArticlePubMedGoogle Scholar
- Santangelo AM, de Souza FvSJ, Franchini LaF, Bumaschny VF, Low MJ, Rubinstein M: Ancient Exaptation of a CORE-SINE Retroposon into a Highly Conserved Mammalian Neuronal Enhancer of the Proopiomelanocortin Gene. PLoS Genetics. 2007, 3 (10): e166-10.1371/journal.pgen.0030166.PubMed CentralView ArticleGoogle Scholar
- Laperriere D, Wang TT, White JH, Mader S: Widespread Alu repeat-driven expansion of consensus DR2 retinoic acid response elements during primate evolution. BMC Genomics. 2007, 8: 23-10.1186/1471-2164-8-23.PubMed CentralView ArticlePubMedGoogle Scholar
- Hamdi HK, Nishio H, Tavis J, Zielinski R, Dugaiczyk A: Alu-mediated phylogenetic novelties in gene regulation and development. J Mol Biol. 2000, 299 (4): 931-939. 10.1006/jmbi.2000.3795.View ArticlePubMedGoogle Scholar
- Adams JS, Chen H, Chun R, Gacad MA, Encinas C, Ren S, Nguyen L, Wu S, Hewison M, Barsony J: Response element binding proteins and intracellular vitamin D binding proteins: novel regulators of vitamin D trafficking, action and metabolism. J Steroid Biochem Mol Biol. 2004, 89–90 (1–5): 461-465. 10.1016/j.jsbmb.2004.03.016.View ArticlePubMedGoogle Scholar
- Arbelle JE, Chen H, Gaead MA, Allegretto EA, Pike JW, Adams JS: Inhibition of vitamin D receptor-retinoid X receptor-vitamin D response element complex formation by nuclear extracts of vitamin D-resistant New World primate cells. Endocrinology. 1996, 137 (2): 786-789. 10.1210/en.137.2.786.PubMedGoogle Scholar
- Chen H, Hu B, Allegretto EA, Adams JS: The vitamin D response element-binding protein. A novel dominant-negative regulator of vitamin D-directed transactivation. J Biol Chem. 2000, 275 (45): 35557-35564. 10.1074/jbc.M007117200.View ArticlePubMedGoogle Scholar
- Babich V, Aksenov N, Alexeenko V, Oei SL, Buchlow G, Tomilin N: Association of some potential hormone response elements in human genes with the Alu family repeats. Gene. 1999, 239 (2): 341-349. 10.1016/S0378-1119(99)00391-1.View ArticlePubMedGoogle Scholar
- Provvedini D, Tsoukas C, Deftos L, Manolagas S: 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science. 1983, 221 (4616): 1181-1183. 10.1126/science.6310748.View ArticlePubMedGoogle Scholar
- Bhalla AK, Amento EP, Clemens TL, Holick MF, Krane SM: Specific high-affinity receptors for 1,25-dihydroxyvitamin D3 in human peripheral blood mononuclear cells: presence in monocytes and induction in T lymphocytes following activation. J Clin Endocrinol Metab. 1983, 57 (6): 1308-1310.View ArticlePubMedGoogle Scholar
- Adams JS, Sharma OP, Gacad MA, Singer FR: Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis. J Clin Invest. 1983, 72 (5): 1856-1860. 10.1172/JCI111147.PubMed CentralView ArticlePubMedGoogle Scholar
- Koeffler HP, Reichel H, Bishop JE, Norman AW: gamma-Interferon stimulates production of 1,25-dihydroxyvitamin D3 by normal human macrophages. Biochem Biophys Res Commun. 1985, 127 (2): 596-603. 10.1016/S0006-291X(85)80202-3.View ArticlePubMedGoogle Scholar
- Tsoukas C, Provvedini D, Manolagas S: 1,25-dihydroxyvitamin D3: a novel immunoregulatory hormone. Science. 1984, 224 (4656): 1438-1440. 10.1126/science.6427926.View ArticlePubMedGoogle Scholar
- Lemire JM, Adams JS, Sakai R, Jordan SC: 1 alpha,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J Clin Invest. 1984, 74 (2): 657-661. 10.1172/JCI111465.PubMed CentralView ArticlePubMedGoogle Scholar
- Amento EP, Bhalla AK, Kurnick JT, Kradin RL, Clemens TL, Holick SA, Holick MF, Krane SM: 1 alpha,25-dihydroxyvitamin D3 induces maturation of the human monocyte cell line U937, and, in association with a factor from human T lymphocytes, augments production of the monokine, mononuclear cell factor. J Clin Invest. 1984, 73 (3): 731-739. 10.1172/JCI111266.PubMed CentralView ArticlePubMedGoogle Scholar
- Rigby WF, Stacy T, Fanger MW: Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxyvitamin D3 (calcitriol). J Clin Invest. 1984, 74 (4): 1451-1455. 10.1172/JCI111557.PubMed CentralView ArticlePubMedGoogle Scholar
- Lemire JM, Archer DC, Beck L, Spiegelberg HL: Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions. J Nutr. 1995, 125 (6 Suppl): 1704S-1708S.PubMedGoogle Scholar
- Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF, O'Garra A: 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol. 2001, 167 (9): 4974-4980.View ArticlePubMedGoogle Scholar
- Penna G, Adorini L: 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol. 2000, 164 (5): 2405-2411.View ArticlePubMedGoogle Scholar
- Staeva-Vieira TP, Freedman LP: 1,25-dihydroxyvitamin D3 inhibits IFN-gamma and IL-4 levels during in vitro polarization of primary murine CD4+ T cells. J Immunol. 2002, 168 (3): 1181-1189.View ArticlePubMedGoogle Scholar
- Daniel C, Sartory NA, Zahn N, Radeke HH, Stein JM: Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and regulatory T cell profile. J Pharmacol Exp Ther. 2008, 324 (1): 23-33. 10.1124/jpet.107.127209.View ArticlePubMedGoogle Scholar
- van Etten E, Mathieu C: Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol. 2005, 97 (1–2): 93-101. 10.1016/j.jsbmb.2005.06.002.View ArticlePubMedGoogle Scholar
- Rajapakse R, Mousli M, Pfaff AW, Uring-Lambert B, Marcellin L, Bronner C, Jeanblanc M, Villard O, Letscher-Bru V, Klein JP, et al: 1,25-Dihydroxyvitamin D3 induces splenocyte apoptosis and enhances BALB/c mice sensitivity to toxoplasmosis. J Steroid Biochem Mol Biol. 2005, 96 (2): 179-185. 10.1016/j.jsbmb.2005.03.002.View ArticlePubMedGoogle Scholar
- Ehrchen J, Helming L, Varga G, Pasche B, Loser K, Gunzer M, Sunderkotter C, Sorg C, Roth J, Lengeling A: Vitamin D receptor signaling contributes to susceptibility to infection with Leishmania major. FASEB J. 2007, 21 (12): 3208-3218. 10.1096/fj.06-7261com.View ArticlePubMedGoogle Scholar
- Hase K, Eckmann L, Leopard JD, Varki N, Kagnoff MF: Cell differentiation is a key determinant of cathelicidin LL-37/human cationic antimicrobial protein 18 expression by human colon epithelium. Infect Immun. 2002, 70 (2): 953-963. 10.1128/IAI.70.2.953-963.2002.PubMed CentralView ArticlePubMedGoogle Scholar
- Erdag G, Morgan JR: Interleukin-1alpha and interleukin-6 enhance the antibacterial properties of cultured composite keratinocyte grafts. Ann Surg. 2002, 235 (1): 113-124. 10.1097/00000658-200201000-00015.PubMed CentralView ArticlePubMedGoogle Scholar
- Sorensen OE, Cowland JB, Theilgaard-Monch K, Liu L, Ganz T, Borregaard N: Wound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors. J Immunol. 2003, 170 (11): 5583-5589.View ArticlePubMedGoogle Scholar
- Schauber J, Svanholm C, Termen S, Iffland K, Menzel T, Scheppach W, Melcher R, Agerberth B, Luhrs H, Gudmundsson GH: Expression of the cathelicidin LL-37 is modulated by short chain fatty acids in colonocytes: relevance of signalling pathways. Gut. 2003, 52 (5): 735-741. 10.1136/gut.52.5.735.PubMed CentralView ArticlePubMedGoogle Scholar
- Islam D, Bandholtz L, Nilsson J, Wigzell H, Christensson B, Agerberth B, Gudmundsson G: Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator. Nat Med. 2001, 7 (2): 180-185. 10.1038/84627.View ArticlePubMedGoogle Scholar
- Chakraborty K, Ghosh S, Koley H, Mukhopadhyay AK, Ramamurthy T, Saha DR, Mukhopadhyay D, Roychowdhury S, Hamabata T, Takeda Y, et al: Bacterial exotoxins downregulate cathelicidin (hCAP-18/LL-37) and human beta-defensin 1 (HBD-1) expression in the intestinal epithelial cells. Cell Microbiol. 2008, 10 (12): 2520-2537. 10.1111/j.1462-5822.2008.01227.x.View ArticlePubMedGoogle Scholar
- Vieth R: What is the optimal vitamin D status for health?. Prog Biophys Mol Biol. 2006, 92 (1): 26-32. 10.1016/j.pbiomolbio.2006.02.003.View ArticlePubMedGoogle Scholar
- Adams JS, Ren S, Liu PT, Chun RF, Lagishetty V, Gombart AF, Borregaard N, Modlin RL, Hewison M: Vitamin d-directed rheostatic regulation of monocyte antibacterial responses. J Immunol. 2009, 182 (7): 4289-4295. 10.4049/jimmunol.0803736.PubMed CentralView ArticlePubMedGoogle Scholar
- Liu PT, Stenger S, Tang DH, Modlin RL: Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol. 2007, 179 (4): 2060-2063.View ArticlePubMedGoogle Scholar
- Sadeghi K, Wessner B, Laggner U, Ploder M, Tamandl D, Friedl J, Zugel U, Steinmeyer A, Pollak A, Roth E, et al: Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol. 2006, 36 (2): 361-370. 10.1002/eji.200425995.View ArticlePubMedGoogle Scholar
- Caivano M, Gorgoni B, Cohen P, Poli V: The induction of cyclooxygenase-2 mRNA in macrophages is biphasic and requires both CCAAT enhancer-binding protein beta (C/EBP beta) and C/EBP delta transcription factors. J Biol Chem. 2001, 276 (52): 48693-48701. 10.1074/jbc.M108282200.View ArticlePubMedGoogle Scholar
- Giovannini L, Panichi V, Migliori M, De Pietro S, Bertelli AA, Fulgenzi A, Filippi C, Sarnico I, Taccola D, Palla R, et al: 1,25-dihydroxyvitamin D(3) dose-dependently inhibits LPS-induced cytokines production in PBMC modulating intracellular calcium. Transplant Proc. 2001, 33 (3): 2366-2368. 10.1016/S0041-1345(01)02023-1.View ArticlePubMedGoogle Scholar
- Takahashi K, Nakayama Y, Horiuchi H, Ohta T, Komoriya K, Ohmori H, Kamimura T: Human neutrophils express messenger RNA of vitamin D receptor and respond to 1alpha,25-dihydroxyvitamin D3. Immunopharmacol Immunotoxicol. 2002, 24 (3): 335-347. 10.1081/IPH-120014721.View ArticlePubMedGoogle Scholar
- Giarratana N, Penna G, Amuchastegui S, Mariani R, Daniel KC, Adorini L: A vitamin D analog down-regulates proinflammatory chemokine production by pancreatic islets inhibiting T cell recruitment and type 1 diabetes development. J Immunol. 2004, 173 (4): 2280-2287.View ArticlePubMedGoogle Scholar
- Mookherjee N, Brown KL, Bowdish DM, Doria S, Falsafi R, Hokamp K, Roche FM, Mu R, Doho GH, Pistolic J, et al: Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37. J Immunol. 2006, 176 (4): 2455-2464.View ArticlePubMedGoogle Scholar
- Tavor S, Park DJ, Gery S, Vuong PT, Gombart AF, Koeffler HP: Restoration of C/EBPalpha expression in a BCR-ABL+ cell line induces terminal granulocytic differentiation. J Biol Chem. 2003, 278 (52): 52651-52659. 10.1074/jbc.M307077200.View ArticlePubMedGoogle Scholar
- Batzer MA, Deininger PL, Hellmann-Blumberg U, Jurka J, Labuda D, Rubin CM, Schmid CW, Zietkiewicz E, Zuckerkandl E: Standardized nomenclature for Alu repeats. J Mol Evol. 1996, 42 (1): 3-6. 10.1007/BF00163204.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.