Intracellular receptor for human host defense peptide LL-37 in monocytes

Neeloffer Mookherjee, Dustin N.D. Lippert, Pamela Hamill, Reza Falsafi, Anastasia Nijnik, Jason Kindrachuk, Jelena Pistolic, Jennifer Gardy, Pegah Miri, Misbah Naseer, Leonard J. Foster, Robert Hancock

Research output: Contribution to journalArticle

104 Citations (Scopus)

Abstract

The human cationic host defense peptide LL-37 has a broad range of immunomodulatory, anti-infective functions. A synthetic innate defense regulator peptide, innate defense regulator 1 (IDR-1), based conceptually on LL-37, was recently shown to selectively modulate innate immunity to protect against a wide range of bacterial infections. Using advanced proteomic techniques, ELISA, and Western blotting procedures, GAPDH was identified as a direct binding partner for LL-37 in monocytes. Enzyme kinetics and mobility shift studies also indicated LL-37 and IDR-1 binding to GAPDH. The functional relevance of GAPDH in peptide-induced responses was demonstrated by using gene silencing of GAPDH with small interfering RNA (siRNA). Previous studies have established that the induction of chemokines and the anti-inflammatory cytokine IL-10 are critical immunomodulatory functions in the anti-infective properties of LL-37 and IDR-1, and these functions are modulated by the MAPK p38 pathway. Consistent with that, this study demonstrated the importance of the GAPDH interactions with these peptides since gene silencing of GAPDH resulted in impaired p38 MAPK signaling, downstream chemokine and cytokine transcriptional responses induced by LL-37 and IDR-1, and LL-37-induced cytokine production. Bioinformatic analysis, using InnateDB, of the major interacting partners of GAPDH indicated the likelihood that this protein can impact on innate immune pathways including p38 MAPK. Thus, this study has demonstrated a novel function for GAPDH as a mononuclear cell receptor for human cathelicidin LL-37 and immunomodulatory IDR-1 and conclusively demonstrated its relevance in the functioning of cationic host defense peptides.

LanguageEnglish
Pages2688-2696
Number of pages9
JournalJournal of Immunology
Volume183
Issue number4
DOIs
Publication statusPublished - 15 Aug 2009
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Mookherjee, N., Lippert, D. N. D., Hamill, P., Falsafi, R., Nijnik, A., Kindrachuk, J., ... Hancock, R. (2009). Intracellular receptor for human host defense peptide LL-37 in monocytes. Journal of Immunology, 183(4), 2688-2696. https://doi.org/10.4049/jimmunol.0802586
Mookherjee, Neeloffer ; Lippert, Dustin N.D. ; Hamill, Pamela ; Falsafi, Reza ; Nijnik, Anastasia ; Kindrachuk, Jason ; Pistolic, Jelena ; Gardy, Jennifer ; Miri, Pegah ; Naseer, Misbah ; Foster, Leonard J. ; Hancock, Robert. / Intracellular receptor for human host defense peptide LL-37 in monocytes. In: Journal of Immunology. 2009 ; Vol. 183, No. 4. pp. 2688-2696.
@article{6e03bd56bf9a4d4d85d4095891eadd15,
title = "Intracellular receptor for human host defense peptide LL-37 in monocytes",
abstract = "The human cationic host defense peptide LL-37 has a broad range of immunomodulatory, anti-infective functions. A synthetic innate defense regulator peptide, innate defense regulator 1 (IDR-1), based conceptually on LL-37, was recently shown to selectively modulate innate immunity to protect against a wide range of bacterial infections. Using advanced proteomic techniques, ELISA, and Western blotting procedures, GAPDH was identified as a direct binding partner for LL-37 in monocytes. Enzyme kinetics and mobility shift studies also indicated LL-37 and IDR-1 binding to GAPDH. The functional relevance of GAPDH in peptide-induced responses was demonstrated by using gene silencing of GAPDH with small interfering RNA (siRNA). Previous studies have established that the induction of chemokines and the anti-inflammatory cytokine IL-10 are critical immunomodulatory functions in the anti-infective properties of LL-37 and IDR-1, and these functions are modulated by the MAPK p38 pathway. Consistent with that, this study demonstrated the importance of the GAPDH interactions with these peptides since gene silencing of GAPDH resulted in impaired p38 MAPK signaling, downstream chemokine and cytokine transcriptional responses induced by LL-37 and IDR-1, and LL-37-induced cytokine production. Bioinformatic analysis, using InnateDB, of the major interacting partners of GAPDH indicated the likelihood that this protein can impact on innate immune pathways including p38 MAPK. Thus, this study has demonstrated a novel function for GAPDH as a mononuclear cell receptor for human cathelicidin LL-37 and immunomodulatory IDR-1 and conclusively demonstrated its relevance in the functioning of cationic host defense peptides.",
author = "Neeloffer Mookherjee and Lippert, {Dustin N.D.} and Pamela Hamill and Reza Falsafi and Anastasia Nijnik and Jason Kindrachuk and Jelena Pistolic and Jennifer Gardy and Pegah Miri and Misbah Naseer and Foster, {Leonard J.} and Robert Hancock",
year = "2009",
month = "8",
day = "15",
doi = "10.4049/jimmunol.0802586",
language = "English",
volume = "183",
pages = "2688--2696",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "4",

}

Mookherjee, N, Lippert, DND, Hamill, P, Falsafi, R, Nijnik, A, Kindrachuk, J, Pistolic, J, Gardy, J, Miri, P, Naseer, M, Foster, LJ & Hancock, R 2009, 'Intracellular receptor for human host defense peptide LL-37 in monocytes', Journal of Immunology, vol. 183, no. 4, pp. 2688-2696. https://doi.org/10.4049/jimmunol.0802586

Intracellular receptor for human host defense peptide LL-37 in monocytes. / Mookherjee, Neeloffer; Lippert, Dustin N.D.; Hamill, Pamela; Falsafi, Reza; Nijnik, Anastasia; Kindrachuk, Jason; Pistolic, Jelena; Gardy, Jennifer; Miri, Pegah; Naseer, Misbah; Foster, Leonard J.; Hancock, Robert.

In: Journal of Immunology, Vol. 183, No. 4, 15.08.2009, p. 2688-2696.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Intracellular receptor for human host defense peptide LL-37 in monocytes

AU - Mookherjee, Neeloffer

AU - Lippert, Dustin N.D.

AU - Hamill, Pamela

AU - Falsafi, Reza

AU - Nijnik, Anastasia

AU - Kindrachuk, Jason

AU - Pistolic, Jelena

AU - Gardy, Jennifer

AU - Miri, Pegah

AU - Naseer, Misbah

AU - Foster, Leonard J.

AU - Hancock, Robert

PY - 2009/8/15

Y1 - 2009/8/15

N2 - The human cationic host defense peptide LL-37 has a broad range of immunomodulatory, anti-infective functions. A synthetic innate defense regulator peptide, innate defense regulator 1 (IDR-1), based conceptually on LL-37, was recently shown to selectively modulate innate immunity to protect against a wide range of bacterial infections. Using advanced proteomic techniques, ELISA, and Western blotting procedures, GAPDH was identified as a direct binding partner for LL-37 in monocytes. Enzyme kinetics and mobility shift studies also indicated LL-37 and IDR-1 binding to GAPDH. The functional relevance of GAPDH in peptide-induced responses was demonstrated by using gene silencing of GAPDH with small interfering RNA (siRNA). Previous studies have established that the induction of chemokines and the anti-inflammatory cytokine IL-10 are critical immunomodulatory functions in the anti-infective properties of LL-37 and IDR-1, and these functions are modulated by the MAPK p38 pathway. Consistent with that, this study demonstrated the importance of the GAPDH interactions with these peptides since gene silencing of GAPDH resulted in impaired p38 MAPK signaling, downstream chemokine and cytokine transcriptional responses induced by LL-37 and IDR-1, and LL-37-induced cytokine production. Bioinformatic analysis, using InnateDB, of the major interacting partners of GAPDH indicated the likelihood that this protein can impact on innate immune pathways including p38 MAPK. Thus, this study has demonstrated a novel function for GAPDH as a mononuclear cell receptor for human cathelicidin LL-37 and immunomodulatory IDR-1 and conclusively demonstrated its relevance in the functioning of cationic host defense peptides.

AB - The human cationic host defense peptide LL-37 has a broad range of immunomodulatory, anti-infective functions. A synthetic innate defense regulator peptide, innate defense regulator 1 (IDR-1), based conceptually on LL-37, was recently shown to selectively modulate innate immunity to protect against a wide range of bacterial infections. Using advanced proteomic techniques, ELISA, and Western blotting procedures, GAPDH was identified as a direct binding partner for LL-37 in monocytes. Enzyme kinetics and mobility shift studies also indicated LL-37 and IDR-1 binding to GAPDH. The functional relevance of GAPDH in peptide-induced responses was demonstrated by using gene silencing of GAPDH with small interfering RNA (siRNA). Previous studies have established that the induction of chemokines and the anti-inflammatory cytokine IL-10 are critical immunomodulatory functions in the anti-infective properties of LL-37 and IDR-1, and these functions are modulated by the MAPK p38 pathway. Consistent with that, this study demonstrated the importance of the GAPDH interactions with these peptides since gene silencing of GAPDH resulted in impaired p38 MAPK signaling, downstream chemokine and cytokine transcriptional responses induced by LL-37 and IDR-1, and LL-37-induced cytokine production. Bioinformatic analysis, using InnateDB, of the major interacting partners of GAPDH indicated the likelihood that this protein can impact on innate immune pathways including p38 MAPK. Thus, this study has demonstrated a novel function for GAPDH as a mononuclear cell receptor for human cathelicidin LL-37 and immunomodulatory IDR-1 and conclusively demonstrated its relevance in the functioning of cationic host defense peptides.

UR - http://www.scopus.com/inward/record.url?scp=70149090684&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.0802586

DO - 10.4049/jimmunol.0802586

M3 - Article

VL - 183

SP - 2688

EP - 2696

JO - Journal of Immunology

T2 - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 4

ER -

Mookherjee N, Lippert DND, Hamill P, Falsafi R, Nijnik A, Kindrachuk J et al. Intracellular receptor for human host defense peptide LL-37 in monocytes. Journal of Immunology. 2009 Aug 15;183(4):2688-2696. https://doi.org/10.4049/jimmunol.0802586