RBCC Red Blood Cell Collection

CAMP (CAP18, FALL39) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Cathelicidin antimicrobial peptide (18 kDa cationic antimicrobial protein; CAP-18; hCAP-18; Antibacterial protein FALL-39; FALL-39 peptide antibiotic; Antibacterial protein LL-37; Flags: Precursor)

UniProt P49913
ID CAMP_HUMAN Reviewed; 170 AA.
AC P49913; Q71SN9;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 1.
DT 22-JAN-2014, entry version 122.
DE RecName: Full=Cathelicidin antimicrobial peptide;
DE AltName: Full=18 kDa cationic antimicrobial protein;
DE Short=CAP-18;
DE Short=hCAP-18;
DE Contains:
DE RecName: Full=Antibacterial protein FALL-39;
DE AltName: Full=FALL-39 peptide antibiotic;
DE Contains:
DE RecName: Full=Antibacterial protein LL-37;
DE Flags: Precursor;
GN Name=CAMP; Synonyms=CAP18, FALL39; ORFNames=HSD26;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND SYNTHESIS OF 132-170.
RC TISSUE=Bone marrow;
RX PubMed=7529412; DOI=10.1073/pnas.92.1.195;
RA Agerberth B., Gunne H., Odeberg J., Kogner P., Boman H.G.,
RA Gudmundsson G.H.;
RT "FALL-39, a putative human peptide antibiotic, is cysteine-free and
RT expressed in bone marrow and testis.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:195-199(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 42-68 AND 83-100.
RC TISSUE=Bone marrow;
RX PubMed=7615076; DOI=10.1016/0014-5793(95)00634-L;
RA Cowland J.B., Johnsen A.H., Borregaard N.;
RT "hCAP-18, a cathelin/pro-bactenecin-like protein of human neutrophil
RT specific granules.";
RL FEBS Lett. 368:173-176(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Bone marrow;
RX PubMed=7890387;
RA Larrick J.W., Hirata M., Balint R.F., Lee J., Zhong J., Wright S.C.;
RT "Human CAP18: a novel antimicrobial lipopolysaccharide-binding
RT protein.";
RL Infect. Immun. 63:1291-1297(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8946956; DOI=10.1016/S0014-5793(96)01199-4;
RA Larrick J.W., Lee J., Ma S., Li X., Francke U., Wright S.C.,
RA Balint R.F.;
RT "Structural, functional analysis and localization of the human CAP18
RT gene.";
RL FEBS Lett. 398:74-80(1996).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=8681941; DOI=10.1111/j.1432-1033.1996.0325z.x;
RA Gudmundsson G.H., Agerberth B., Odeberg J., Bergman T., Olsson B.,
RA Salcedo R.;
RT "The human gene FALL39 and processing of the cathelin precursor to the
RT antibacterial peptide LL-37 in granulocytes.";
RL Eur. J. Biochem. 238:325-332(1996).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Epididymis;
RA Gao Y., Huang Y.F., Xia X.Y.;
RL Submitted (OCT-2002) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RA Wu N., Miao S.Y., Zhang X.D., Qiao Y., Liang G., Wang L.F.;
RT "A new spermatogenesis-related gene.";
RL Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11238224; DOI=10.1128/CDLI.8.2.370-375.2001;
RA Bals R., Lang C., Weiner D.J., Vogelmeier C., Welsch U., Wilson J.M.;
RT "Rhesus monkey (Macaca mulatta) mucosal antimicrobial peptides are
RT close homologues of human molecules.";
RL Clin. Diagn. Lab. Immunol. 8:370-375(2001).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S.,
RA Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W.,
RA Korn B., Zuo D., Hu Y., LaBaer J.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP STRUCTURE BY NMR OF 146-170, AND FUNCTION.
RX PubMed=16637646; DOI=10.1021/ja0584875;
RA Li X., Li Y., Han H., Miller D.W., Wang G.;
RT "Solution structures of human LL-37 fragments and NMR-based
RT identification of a minimal membrane-targeting antimicrobial and
RT anticancer region.";
RL J. Am. Chem. Soc. 128:5776-5785(2006).
RN [12]
RP STRUCTURE BY NMR OF 134-170, AND FUNCTION.
RX PubMed=18818205; DOI=10.1074/jbc.M805533200;
RA Wang G.;
RT "Structures of human host defense cathelicidin LL-37 and its smallest
RT antimicrobial peptide KR-12 in lipid micelles.";
RL J. Biol. Chem. 283:32637-32643(2008).
CC -!- FUNCTION: Binds to bacterial lipopolysaccharides (LPS), has
CC antibacterial activity.
CC -!- INTERACTION:
CC P08069:IGF1R; NbExp=3; IntAct=EBI-6378485, EBI-475981;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Expressed in bone marrow and testis and
CC neutrophils.
CC -!- PTM: The N-terminus is blocked.
CC -!- SIMILARITY: Belongs to the cathelicidin family.
CC -!- CAUTION: PubMed:11238224 sequence was incorrectly assigned to
CC originate from M.mulatta.
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DR EMBL; Z38026; CAA86115.1; -; mRNA.
DR EMBL; X89658; CAA61805.1; -; mRNA.
DR EMBL; U19970; AAA74084.1; -; mRNA.
DR EMBL; U48795; AAC02634.1; -; Genomic_DNA.
DR EMBL; X96735; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AY162210; AAN78318.1; -; mRNA.
DR EMBL; AY251531; AAP20054.1; -; mRNA.
DR EMBL; AF288284; AAG40802.1; -; mRNA.
DR EMBL; CR457083; CAG33364.1; -; mRNA.
DR EMBL; CR541961; CAG46759.1; -; mRNA.
DR EMBL; BC055089; AAH55089.1; -; mRNA.
DR PIR; I38932; I38932.
DR PIR; S74248; S74248.
DR RefSeq; NP_004336.3; NM_004345.4.
DR UniGene; Hs.51120; -.
DR PDB; 2FBS; NMR; -; N=150-162.
DR PDB; 2FBU; NMR; -; H=134-145.
DR PDB; 2FCG; NMR; -; F=146-170.
DR PDB; 2K6O; NMR; -; A=134-170.
DR PDB; 2LMF; NMR; -; A=134-156.
DR PDB; 4EYC; X-ray; 1.90 A; A/B=31-133.
DR PDBsum; 2FBS; -.
DR PDBsum; 2FBU; -.
DR PDBsum; 2FCG; -.
DR PDBsum; 2K6O; -.
DR PDBsum; 2LMF; -.
DR PDBsum; 4EYC; -.
DR DisProt; DP00004; -.
DR ProteinModelPortal; P49913; -.
DR SMR; P49913; 31-130, 134-170.
DR IntAct; P49913; 2.
DR STRING; 9606.ENSP00000296435; -.
DR TCDB; 1.C.33.1.10; the cathelicidin (cathelicidin) family.
DR DMDM; 1706745; -.
DR PaxDb; P49913; -.
DR PRIDE; P49913; -.
DR DNASU; 820; -.
DR Ensembl; ENST00000576243; ENSP00000458149; ENSG00000164047.
DR GeneID; 820; -.
DR KEGG; hsa:820; -.
DR CTD; 820; -.
DR GeneCards; GC03P048264; -.
DR HGNC; HGNC:1472; CAMP.
DR HPA; CAB015949; -.
DR HPA; CAB016522; -.
DR HPA; HPA029874; -.
DR MIM; 600474; gene.
DR neXtProt; NX_P49913; -.
DR PharmGKB; PA26054; -.
DR eggNOG; NOG40811; -.
DR HOGENOM; HOG000093184; -.
DR HOVERGEN; HBG006116; -.
DR InParanoid; P49913; -.
DR KO; K13916; -.
DR Reactome; REACT_116125; Disease.
DR EvolutionaryTrace; P49913; -.
DR GeneWiki; Cathelicidin; -.
DR GenomeRNAi; 820; -.
DR NextBio; 3356; -.
DR PMAP-CutDB; P49913; -.
DR PRO; PR:P49913; -.
DR ArrayExpress; P49913; -.
DR Bgee; P49913; -.
DR CleanEx; HS_CAMP; -.
DR Genevestigator; P49913; -.
DR GO; GO:0005618; C:cell wall; TAS:Reactome.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0042742; P:defense response to bacterium; TAS:ProtInc.
DR GO; GO:0051701; P:interaction with host; TAS:Reactome.
DR GO; GO:0051873; P:killing by host of symbiont cells; IDA:MGI.
DR GO; GO:0044140; P:negative regulation of growth of symbiont on or near host surface; IDA:MGI.
DR GO; GO:0090382; P:phagosome maturation; TAS:Reactome.
DR InterPro; IPR001894; Cathelicidin.
DR InterPro; IPR018216; Cathelicidin_CS.
DR InterPro; IPR022746; Cathlecidin_C.
DR PANTHER; PTHR10206; PTHR10206; 1.
DR Pfam; PF12153; CAP18_C; 1.
DR Pfam; PF00666; Cathelicidins; 1.
DR ProDom; PD001838; Cathelicidin; 1.
DR PROSITE; PS00946; CATHELICIDINS_1; 1.
DR PROSITE; PS00947; CATHELICIDINS_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Antibiotic; Antimicrobial;
KW Cleavage on pair of basic residues; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Reference proteome;
KW Secreted; Signal.
FT SIGNAL 1 30 Potential.
FT PROPEP 31 131
FT /FTId=PRO_0000004722.
FT CHAIN 132 170 Antibacterial protein FALL-39.
FT /FTId=PRO_0000004723.
FT CHAIN 134 170 Antibacterial protein LL-37.
FT /FTId=PRO_0000004724.
FT DISULFID 86 97 By similarity.
FT DISULFID 108 125 By similarity.
FT CONFLICT 6 6 D -> N (in Ref. 1, 6, 7 and 9; CAG46759).
FT HELIX 35 49
FT STRAND 53 61
FT STRAND 75 87
FT HELIX 94 96
FT STRAND 105 112
FT STRAND 122 126
FT HELIX 136 140
FT HELIX 151 161
SQ SEQUENCE 170 AA; 19301 MW; 055B07DCA95A7D16 CRC64;
MKTQRDGHSL GRWSLVLLLL GLVMPLAIIA QVLSYKEAVL RAIDGINQRS SDANLYRLLD
LDPRPTMDGD PDTPKPVSFT VKETVCPRTT QQSPEDCDFK KDGLVKRCMG TVTLNQARGS
FDISCDKDNK RFALLGDFFR KSKEKIGKEF KRIVQRIKDF LRNLVPRTES
//

MIM 600474
*RECORD*
*FIELD* NO
600474
*FIELD* TI
*600474 CATHELICIDIN ANTIMICROBIAL PEPTIDE; CAMP
;;CATIONIC ANTIMICROBIAL PROTEIN, 18-KD; CAP18;;
read moreCRAMP, MOUSE, HOMOLOG OF; CRAMP
LL37, INCLUDED;;
PEPTIDE ANTIBIOTIC, PR-39, PORCINE, HOMOLOG OF, INCLUDED; FALL39,
INCLUDED
*FIELD* TX

DESCRIPTION

Antimicrobial peptides, such as cathelicidins, are secreted by activated
epithelial cells and invading leukocytes and play an important role in
host defense. Like other cathelicidins, the full-length CAMP protein
(also called CAP18) consists of an N-terminal signal peptide, a
conserved cathelin-like domain, and a C-terminal antimicrobial domain
corresponding to the mature antimicrobial peptide. The mature
antimicrobial peptide cleaved from full-length CAMP, LL37, promotes
inflammation, angiogenesis, wound healing, and tumor metastasis (summary
by Subramanian et al., 2011).

CLONING

Animal peptide antibiotics can functionally be divided into 2 groups:
those that accumulate in the granule of phagocytes and kill engulfed
microbes (e.g., HNP1; 125220), and those that are delivered into body
fluids or epithelial layers (e.g., DEF5; 600472). By PCR screen of a
human cDNA library, Agerberth et al. (1995) isolated FALL39, the human
counterpart of the PR-39 animal peptide antibiotic found in pig
intestine. FALL39, named for the first 4 N-terminal amino acids
(phe-ala-leu-leu) and the total number of residues (39), is a peptide
predicted to contain an amphipathic alpha helix. FALL39 lacks cysteine,
making it different from all other previously isolated human peptide
antibiotics of the defensin family, each of which contain 3 disulfide
bridges. Agerberth et al. (1995) chemically synthesized the FALL39
peptide from the predicted amino acid sequence and showed it to be
antibacterial. Zanetti et al. (1993) reported that a number of
antibacterial peptides from different mammals contained a conserved
pro-region very similar to cathelin, a cysteine protease inhibitor
isolated from pig leukocytes. Agerberth et al. (1995) showed that
prepro-FALL39 encodes a cathelin-like precursor protein consisting of
170 amino acids. By RNA blot analysis, they found that the gene for
FALL39 is expressed mainly in bone marrow and testis, tissues that are
not often sites of infection. Interestingly, other species (e.g., bull
and Drosophila) express antibacterial proteins in reproductive organs as
well. With resistance to classic antibiotics becoming a clinical
problem, Agerberth et al. (1995) suggested that the peptide FALL39 (or
even a fragment, such as the amphipathic alpha helix) has the potential
to become an antibacterial drug.

Larrick et al. (1996) independently cloned the human CAP18 gene from a
human genomic phage library. Sequence analysis revealed that, like
several other genes expressed late in polymorphonuclear leukocyte
development, the CAP18 gene does not contain typical TATA box or CCAAT
sequences. Western, Northern, and RT-PCR analysis showed that CAP18 is
produced specifically in granulocytes. The family of CAP18 proteins
share a similar overall structure: signal sequence, conserved N-terminal
protein sequence of unknown function, and a C-terminal antimicrobial
domain.

GENE STRUCTURE

Gudmundsson et al. (1996) characterized and sequenced the complete human
FALL39 gene. It is a compact gene of 1,963 bp with 4 exons. Exons 1-3
encode for a signal sequence and the cathelin region. Exon 4 contains
the information for the mature antibacterial peptide. Their results
suggested that FALL39 is the only member of the cathelin gene family
present in the human genome. Potential binding sites for
acute-phase-response factors were identified in the promoter and in
intron 2. Anti-(FALL39) IgG located the peptide in granulocytes and the
mature peptide was isolated from these cells after degranulation.

MAPPING

Larrick et al. (1996) mapped the CAMP gene to 3p21.3 by fluorescence in
situ hybridization.

GENE FUNCTION

Frohm et al. (1997) demonstrated upregulation of human CAMP in
inflammatory skin disorders, whereas in normal skin no induction was
found. By in situ hybridization and immunohistochemistry, the transcript
and the peptide were located in keratinocytes throughout the epidermis
of the inflammatory regions. In addition, the peptide was detected in
partially pure fractions derived from psoriatic scales by
immunoblotting. Fractions expressing CAMP also exhibited antibacterial
activity. Frohm et al. (1997) proposed a protective role for CAMP, when
the integrity of the skin barrier is damaged, participating in the first
line of defense, and preventing local infection and systemic invasion of
microbes.

Sorensen et al. (2001) found that CAMP is cleaved by proteinase-3
(177020) to generate the antimicrobial peptide LL-37. Proteinase-3 is
the only 1 of the 3 known serine proteases from azurophil granules that
has this function. The cleavage takes place after exocytosis, i.e., it
occurs extracellularly. Bovine and porcine cathelicidins are cleaved by
elastase from the azurophil granules to yield the active antimicrobial
peptides. Thus, active antimicrobial peptides are generated from common
proproteins differently in these related species.

Niyonsaba et al. (2002) showed that LL-37 not only induces rat mast cell
degranulation, but it also has dose-dependent chemotactic, but not
chemokinetic, effects on these cells by utilizing a Gi
protein-phospholipase C signaling pathway. Scatchard analysis indicated
that LL-37 has both high- and low-affinity receptors that are distinct
from FPRL1 (136538), a receptor used by the peptide on neutrophils and
granulocytes. Niyonsaba et al. (2002) proposed that LL-37 may recruit
mast cells to sites of inflammation.

By flow cytometric analysis, Nagaoka et al. (2001) showed that
expression of human CAMP and guinea pig Cap11 inhibits
lipopolysaccharide (LPS) binding to a murine macrophage cell line.
Northern and Western blot analyses revealed that CAMP and Cap11 inhibit
LPS-induced TNF (191160) expression. Binding analysis indicated that
CAMP and Cap11 bind to CD14 (158120) and suppress LPS interaction with
LPS-binding protein (LBP; 151990). In a mouse model, Nagaoka et al.
(2001) confirmed the results of Kirikae et al. (1998) by showing that
CAMP administration reversed the 90% lethality of LPS to 80% survival
and lowered serum TNF levels. Nagaoka et al. (2001) proposed that CAMP,
Cap11, and their derivatives could be candidates for adjunctive therapy
in gram-negative bacterial sepsis.

Koczulla et al. (2003) demonstrated that application of CAMP resulted in
neovascularization in the chorioallantoic membrane assay and in a rabbit
model of hindlimb ischemia. The peptide directly activated endothelial
cells, resulting in increased proliferation and formation of vessel-like
structures in cultivated endothelial cells. There was decreased
vascularization during wound healing in mice deficient in Camp. Koczulla
et al. (2003) concluded that CAMP is a multifunctional antimicrobial
peptide with a central role in innate immunity by linking host defense
and inflammation with angiogenesis and arteriogenesis.

Wang et al. (2004) showed that the active hormonal form of vitamin D,
1,25(OH)2D3, directly induced CAMP and DEFB2 (602215) expression and
activity in keratinocytes, monocytes, and neutrophils through consensus
vitamin D response elements in the promoters of the 2 genes. RT-PCR
detected synergistic enhancement of antimicrobial peptide expression in
neutrophils stimulated with 1,25(OH)2D3 and LPS.

While humans and mice have only 1 CAMP gene, domesticated mammals such
as pig, cow, and horse have multiple Camp genes. By overexpression in
human keratinocytes, Lee et al. (2005) found that Pr39, a porcine Camp,
acted additively with human LL37 to kill group A Streptococcus.
Transgenic mice expressing Pr39 showed increased resistance to group A
Streptococcus skin infection, whereas mice overexpressing their native
Camp did not. Lee et al. (2005) concluded that gene transfer of
xenobiotic Camp confers resistance against infection.

Using DNA microarray and quantitative PCR analyses, Liu et al. (2006)
found that activation of TLR2 (603028) and TLR1 (601194) by a
mycobacterial ligand upregulated expression of vitamin D receptor (VDR;
601769) and CYP27B1 (609506), the vitamin D 1-hydroxylase that catalyzes
the conversion of vitamin D to its active form, in monocytes and
macrophages, but not dendritic cells. Intracellular flow cytometric and
quantitative PCR analyses showed that treatment of monocytes with
vitamin D upregulated expression of CYP24 (CYP24A1; 126065), the vitamin
D 24-hydroxylase, and CAMP, but not DEFB4 (602215). Confocal microscopy
demonstrated colocalization of CAMP with bacteria-containing vacuoles of
vitamin D-treated monocytes, and vitamin D treatment of M.
tuberculosis-infected macrophages reduced the number of viable bacilli.
Ligand stimulation of TLR2 and TLR1 upregulated CYP24 and CAMP in the
presence of human serum, but not bovine serum, and CAMP upregulation was
more efficient in Caucasian than in African American serum, in which
vitamin D levels were significantly lower. Vitamin D supplementation of
African American serum reversed the CAMP induction defect. Liu et al.
(2006) proposed that vitamin D supplementation in African and Asian
populations, which may have a reduced ability to synthesize vitamin D
from ultraviolet light in sunlight, might be an effective and
inexpensive intervention to enhance innate immunity against microbial
infection and neoplastic disease.

By immunohistochemical analysis, Chromek et al. (2006) found that
epithelial cells in the human urinary tract produced CAMP and rapidly
secreted it in response to uropathogenic bacteria. Mice also secreted
Cramp during urinary tract infection. Both synthetic mouse and human
CAMP killed uropathogenic E. coli. Mice lacking Cramp had significantly
higher levels of bacteria in bladder and were not aided by the presence
of neutrophils expressing Cramp. Cramp-deficient mice lost weight and
were prone to septicemia and death in response to infection, whereas all
wildtype mice survived. Chromek et al. (2006) concluded that CAMP is
important in bacterial clearance of the urinary tract.

Atopic dermatitis (AD; see 603165) is associated with eczema vaccinatum,
a disseminated viral skin infection that follows innoculation with
vaccinia virus (VV). Using real-time RT-PCR, Howell et al. (2006) found
that skin from AD patients had significantly increased VV expression and
reduced LL37 expression compared with skin from healthy controls or
patients with psoriasis (see 177900). IL4 (147780) and IL13 (147683)
enhanced VV expression and downregulated LL37 in VV-stimulated
keratinocytes. Neutralization of IL4 and IL13 in AD skin augmented LL37
expression and inhibited VV replication. Howell et al. (2006) found that
LL37 was induced via TLR3 (603029) and was inhibited by IL4 and IL13
through STAT6 (601512). Skin from mice lacking the murine LL37 homolog,
Cramp, showed reduced ability to control VV replication, and Cramp
production was reduced in Tlr3-deficient mice. Exogenous LL37 controlled
VV replication in infected keratinocytes and in AD skin explants. Howell
et al. (2006) concluded that Th2 cytokines enhance VV replication in AD
skin by subverting the innate immune response against VV in a
STAT6-dependent manner.

Lande et al. (2007) identified the antimicrobial peptide LL37 as the key
factor that mediates plasmacytoid dendritic cell activation in
psoriasis, a common autoimmune disease of the skin. LL37 converts inert
self-DNA into a potent trigger of interferon production by binding the
DNA to form aggregated and condensed structures that are delivered to
and retained within early endocytic compartments in plasmacytoid
dendritic cells to trigger Toll-like receptor-9 (605474). Lande et al.
(2007) concluded that their data uncovered a fundamental role of an
endogenous antimicrobial peptide in breaking innate tolerance to
self-DNA and suggested that this pathway may drive autoimmunity in
psoriasis.

Acne rosacea is an inflammatory disease that affects 3% of the U.S.
population over 30 years of age and is characterized by erythema,
papulopustules, and telangiectasia. Yamasaki et al. (2007) showed that
individuals with rosacea express abnormally high levels of cathelicidin
in their facial skin and that the proteolytically processed forms of
cathelicidin peptides found in rosacea are different from those present
in normal individuals. These cathelicidin peptides are a result of a
posttranslational processing abnormality associated with an increase in
stratum corneum tryptic enzyme (SCTE; 605643) in the epidermis. In mice,
injection of the cathelicidin peptides found in rosacea, addition of
SCTE, and increasing protease activity by targeted deletion of the
serine protease inhibitor gene Spink5 (605010) each increases
inflammation in mouse skin. The role of cathelicidin in inhibiting
SCTE-mediated inflammation was verified in mice with a targeted deletion
of Camp, the gene encoding cathelicidin. Yamasaki et al. (2007)
concluded that their findings confirmed the role of cathelicidin in skin
inflammatory responses and suggested an explanation for the pathogenesis
of rosacea by demonstrating that an exacerbated innate immune response
can reproduce elements of this disease.

Using proteomic techniques, ELISA, and Western blot analysis, Mookherjee
et al. (2009) identified GAPDH (138400) as a direct binding partner for
LL37 in human monocytes. Enzyme kinetics and mobility shift studies also
showed that LL37 and its synthetic counterpart, IDR1, bound to GAPDH.
Silencing of GAPDH impaired p38 MAPK (MAPK14; 600289) signaling and p38
MAPK-dependent chemokine and cytokine responses. Mookherjee et al.
(2009) concluded that GAPDH is a mononuclear cell receptor for LL37 and
is involved in the functioning of cationic host defense peptides.

Subramanian et al. (2011) reported that a human mast cell line
expressing MRGX2 (MRGPRX2; 607228), as well as mast cells derived from
pluripotent stem cells, responded to LL37 for sustained Ca(2+)
mobilization and degranulation. In contrast, an immature mast cell line
lacking MRGX2 and a mast cell line treated with short hairpin RNA
(shRNA) against MRGX2 did not respond to LL37. Mast cell lines stably
expressing MRGX2 responded to LL37 by chemotaxis, degranulation, and
CCL4 (182284) production. MRGX2 resisted LL37-induced phosphorylation,
desensitization, and internalization. Knockdown of GPCR kinase-2 (GRK2,
or ADRBK1; 109635) and GRK3 (ADRBK2; 109636) via shRNA had no effect on
mast cell degranulation induced by LL37. Subramanian et al. (2011)
concluded that MRGX2 is a novel GPCR for LL37 that differs from other
GPCRs in that it is resistant to agonist-induced receptor
phosphorylation, desensitization, and internalization.

ANIMAL MODEL

The mouse gene Cnlp is similar to human CAMP and encodes a peptide
called Cramp. The 2 proteins have similar alpha-helical structures,
spectra of antimicrobial activity, and tissue distribution. Nizet et al.
(2001) generated Cnlp-null mice by targeted disruption. These mice had
normal fetal development, were fertile, survived into adulthood, and
demonstrated no obvious phenotype when housed under aseptic
barrier-controlled conditions. Exposure to subcutaneous administration
of Group A Streptococcus resulted in severe Group A Streptococcus
infection. Similarly, infection of wildtype mice with Cramp-resistant
Group A Streptococcus mutants resulted in more severe infections in
these animals. Blood leukocytes of Cnlp-null mice were equivalent in
relative number in oxidative burst capacity but were deficient in
bacterial killing when compared to leukocytes derived from wildtype
mice. Nizet et al. (2001) concluded that the specific antimicrobial
activity of cathelicidin is itself necessary for bacterial clearance and
innate skin immunity.

*FIELD* RF
1. Agerberth, B.; Gunne, H.; Odeberg, J.; Kogner, P.; Boman, H. G.;
Gudmundsson, G. H.: FALL-39, a putative human peptide antibiotic,
is cysteine-free and expressed in bone marrow and testis. Proc. Nat.
Acad. Sci. 92: 195-199, 1995.

2. Chromek, M.; Slamova, Z.; Bergman, P.; Kovacs, L.; Podracka, L.;
Ehren, I.; Hokfelt, T.; Gudmundsson, G. H.; Gallo, R. L.; Agerberth,
B.; Brauner, A.: The antimicrobial peptide cathelicidin protects
the urinary tract against invasive bacterial infection. Nature Med. 12:
636-641, 2006.

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*FIELD* CN
Matthew B. Gross - updated: 5/4/2012
Paul J. Converse - updated: 5/3/2012
Paul J. Converse - updated: 11/15/2010
Ada Hamosh - updated: 3/26/2008
Ada Hamosh - updated: 10/9/2007
Paul J. Converse - updated: 11/9/2006
Paul J. Converse - updated: 7/20/2006
Paul J. Converse - updated: 4/12/2006
Paul J. Converse - updated: 1/6/2006
Patricia A. Hartz - updated: 4/27/2005
Marla J. F. O'Neill - updated: 3/17/2005
Paul J. Converse - updated: 5/14/2002
Paul J. Converse - updated: 1/18/2002
Ada Hamosh - updated: 11/26/2001
Victor A. McKusick - updated: 8/7/2001
Ada Hamosh - updated: 5/29/2000
Ethylin Wang Jabs - updated: 8/21/1997

*FIELD* CD
Victor A. McKusick: 3/30/1995

*FIELD* ED
terry: 09/07/2012
mgross: 5/4/2012
terry: 5/3/2012
mgross: 11/15/2010
terry: 11/15/2010
alopez: 3/28/2008
terry: 3/26/2008
alopez: 10/17/2007
terry: 10/9/2007
mgross: 11/10/2006
terry: 11/9/2006
mgross: 8/4/2006
terry: 7/20/2006
mgross: 4/12/2006
mgross: 1/6/2006
mgross: 4/27/2005
wwang: 3/17/2005
wwang: 3/16/2005
mgross: 3/31/2003
mgross: 5/14/2002
mgross: 1/18/2002
alopez: 11/26/2001
terry: 11/26/2001
mcapotos: 8/10/2001
mcapotos: 8/9/2001
terry: 8/7/2001
alopez: 6/2/2000
terry: 5/29/2000
mark: 9/5/1997
jamie: 2/12/1997
jamie: 12/4/1996
terry: 11/11/1996
mark: 3/30/1995