Involvement of P2X7 purinergic receptor and MEK1/2 in interleukin-8 up-regulation by LL-37 in human gingival fibroblasts

Montreekachon, Pattanin; Chotjumlong, Pareena; Bolscher, Jan G. M.; Nazmi, Kamran; Reutrakul, Vichai; Krisanaprakornkit, Suttichai

doi:10.1111/j.1600-0765.2011.01346.x

Cited by 55 publications

(47 citation statements)

References 45 publications

(65 reference statements)

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“…Although LL-37 mediates its responses in most immune cells and endothelial cells via FPR2, it activates CXCR2 in neutrophils, insulin growth factor receptor in gingival fibroblasts, and P2X7 in transfected HEK293 cells (8,(11)(12)(13)(14)47). LL-37 induces chemotaxis, degranulation and chemokine production in mast cells (17-19, 22, 23).…”

Section: Discussionmentioning

confidence: 99%

“…Most effects of LL-37 appear to be mediated via the activation of G protein-coupled formyl peptide receptor 2 (FPR2; earlier known as FPRL1) on monocytes, T cells, and endothelial cells (3, 8 -11). LL-37 also activates chemokine receptor CXCR2 in human neutrophils (12), purinergic receptor P2X7 in fibroblasts (13), and insulin growth factor receptors in epithelial cells (14).…”

mentioning

confidence: 99%

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Mas-related Gene X2 (MrgX2) Is a Novel G Protein-coupled Receptor for the Antimicrobial Peptide LL-37 in Human Mast Cells

Subramanian

Gupta

Guo

et al. 2011

Journal of Biological Chemistry

196

241

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Background: Antimicrobial peptide LL-37 activates leukocytes, mast cells, and endothelial cells. Results: LL-37 causes chemotaxis, degranulation, and chemokine production in human mast cells expressing MrgX2, but it does not induce receptor desensitization. Conclusion: MrgX2 is a novel receptor for LL-37 in human mast cells, and this receptor is resistant to regulation. Significance: This study has important implications for innate immunity and inflammation.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Mas-related Gene X2 (MrgX2) Is a Novel G Protein-coupled Receptor for the Antimicrobial Peptide LL-37 in Human Mast Cells

Subramanian

Gupta

Guo

et al. 2011

Journal of Biological Chemistry

196

241

View full text Add to dashboard Cite

show abstract

“…HGFs were then trypsinized, and their number was expanded for subsequent experiments. For cell treatment, HGFs were starved from FBS for 6 h prior to treatment with non-toxic doses of LL-37, as previously reported [21], or 1 ng/ml of IL-1β in the presence or absence of pharmacological inhibitors for specific times, since it has previously been shown that FBS can induce COX-2 expression and PGE 2 production [22]. …”

Section: Methodsmentioning

confidence: 99%

Involvement of the P2X<sub>7</sub> Purinergic Receptor and c-Jun N-Terminal and Extracellular Signal-Regulated Kinases in Cyclooxygenase-2 and Prostaglandin E<sub>2</sub> Induction by LL-37

Chotjumlong¹,

Bolscher²,

Nazmi³

et al. 2012

J Innate Immun

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Periodontal disease is caused by microorganisms and host-derived inflammation involving increased cyclooxygenase-2 (COX-2) expression and prostaglandin E₂ (PGE₂) production. We previously demonstrated that human β-defensin-3 induces COX-2 and PGE₂ in human gingival fibroblasts (HGFs). We, therefore, aimed to examine the inducible effects of LL-37, the only cathelicidin expressed in humans, on COX-2 expression and PGE₂ synthesis in HGFs and to elucidate the relevant signaling pathways. The COX-2 expression was upregulated by LL-37 in dose- and time-dependent manners. Accordingly, the synthesis of PGE₂ in cell-free culture supernatants was raised by LL-37 (p < 0.01) and blocked by NS-398, a specific COX-2 inhibitor (p < 0.01). P2X inhibitors and a neutralizing antibody against P2X₇ purinergic receptor significantly abrogated COX-2 induction and PGE₂ production by LL-37 (p < 0.01). LL-37 upregulated COX-2 expression and PGE₂ synthesis via activation of extracellular signal-regulated kinase (ERK) and p46 c-Jun N-terminal kinase (JNK), while interleukin-1β did so via nuclear factor-ĸB and all three mitogen-activated protein kinases. In summary, LL-37 can control arachidonic acid metabolism by induction of COX-2 expression and PGE₂ synthesis via the P2X₇ receptor, ERK, and p46 JNK. The pro-inflammatory effects of LL-37 may be essential for initiating oral mucosal inflammation in periodontal disease.

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“…Stimulation of the P2X 7 R in gingival fibroblasts was also implicated in the up-regulation of IL-8 by the antimicrobial peptide LL-37 (Montreekachon et al, 2011). LL-37 can attract leukocytes and up-regulate immune-related genes in various cell types (Zanetti, 2004), and levels of LL-37 are perturbed in periodontitis (Puklo et al, 2008).…”

Section: Atp and Gingival Cellsmentioning

confidence: 99%

Inflammation, Pain, and Pressure—Purinergic Signaling in Oral Tissues

Lim

Mitchell

2012

J Dent Res

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Signaling by extracellular purines such as ATP and adenosine has implications for dental research on multiple levels, with the association of purinergic signaling with inflammation, mechanical strain, and pain making the system particularly relevant for the specific challenges in the oral cavity. Oral tissues express a variety of G-protein-coupled P2Y receptors for ATP and P1 receptors for adenosine in addition to ionotropic P2X receptors for ATP. When these receptors are combined with the plethora of extracellular enzymes capable of manipulating extracellular agonist levels, a complex system for regulating oral health emerges, and recent findings have begun to identify a key role for purinergic signaling in oral pathophysiology. For example, the manipulation of extracellular ATP levels by P. gingivalis reduces inflammasome activation and apoptosis linked to P2X 7 receptor activation. Release of ATP by periodontal ligaments may link mechanical strain to bone remodeling. Activation of P2X receptors is implicated in dental pain, and receptor antagonists represent important targets for new analgesics. Altered levels of adenosine receptors in periodontal disease also suggest a role for nucleosides in dental signaling. The intricacies of the purinergic signaling system make it well-suited for the unique concerns of dental research, and future findings will doubtless confirm this importance.

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Involvement of P2X7 purinergic receptor and MEK1/2 in interleukin-8 up-regulation by LL-37 in human gingival fibroblasts

Abstract: These findings indicate that LL-37 induces IL-8 expression via the P2X(7) receptor and the MEK1/2-dependent p44/42 MAP kinases in HGFs, suggesting both direct and indirect involvement of LL-37 in neutrophil recruitment into an inflammatory site within diseased periodontal tissues.

Cited by 55 publications

References 45 publications

Mas-related Gene X2 (MrgX2) Is a Novel G Protein-coupled Receptor for the Antimicrobial Peptide LL-37 in Human Mast Cells

Mas-related Gene X2 (MrgX2) Is a Novel G Protein-coupled Receptor for the Antimicrobial Peptide LL-37 in Human Mast Cells

Involvement of the P2X<sub>7</sub> Purinergic Receptor and c-Jun N-Terminal and Extracellular Signal-Regulated Kinases in Cyclooxygenase-2 and Prostaglandin E<sub>2</sub> Induction by LL-37

Inflammation, Pain, and Pressure—Purinergic Signaling in Oral Tissues

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