title: Human antimicrobial peptide LL-37 induces glial-mediated neuroinflammation.
abstract: LL-37 is the sole cathelicidin-derived antimicrobial peptide found in humans. It becomes active upon C-terminal cleavage of its inactive precursor hCAP18. In addition to antimicrobial action, it also functions as an innate immune system stimulant in many tissues of the body. Here we report that hCAP18 and LL-37 are expressed in all organs of the human body that were studied with the highest basic levels being expressed in the GI tract and the brain. Its expression and functional role in the central nerve system (CNS) has not previously been reported. We found increased expression of LL-37 in IFNγ-stimulated human astrocytes and their surrogate U373 cells, as well as in LPS/IFNγ-stimulated human microglia and their surrogate monocyte-derived THP-1 cells. We found that treatment of microglia, astrocytes, THP-1 cells and U373 cells with LL-37 induced secretion of the inflammatory cytokines IL-1β and IL-6; the chemokines IL-8 and CCL-2, and other materials toxic to human neuroblastoma SH-SY5Y cells. The mechanism of LL-37 stimulation involves activation of intracellular proinflammatory pathways involving phospho-P38 MAP kinase and phospho-NFκB proteins. We blocked the inflammatory stimulant action of LL-37 by removing it with an anti-LL-37 antibody. The inflammatory effect was also prevented by treatment with inhibitors of PKC, PI3K and MEK-1/2 as well as with the intracellular Ca(2+)-chelator, BAPTA-AM. This indicates involvement of these intracellular pathways. Our data suggest that LL-37, in addition to its established roles, may play a role in the chronic neuroinflammation which is observed in neurodegenerative diseases such as Alzheimer's and Parkinson's disease.
authors: Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3.
authors: Moonhee
authors: M
authors: Lee
authors: Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3.
authors: Xiaolei
authors: X
authors: Shi
authors: Department of Bioengineering, Stanford University, Stanford, CA 94305, United States.
authors: Annelise E
authors: AE
authors: Barron
authors: Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3.
authors: Edith
authors: E
authors: McGeer
authors: Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3. Electronic address: mcgeerpl@mail.ubc.ca.
authors: Patrick L
authors: PL
authors: McGeer
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004660:Encephalitis / Q000139:chemically induced*; D006801:Humans; D009457:Neuroglia / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D017931:DNA Primers; D054804:Cathelicidins
keywords: Astrocytes; Cathelicidin; Chemokines; Inflammatory cytokines; Microglia