Cathelicidin rCRAMP stimulates rat mast cells to generate cysteinyl leukotrienes, synthesize TNF and migrate: involvement of PLC/A2, PI3K and MAPK signaling pathways

Abstract

Cathelicidins represent a family of cationic peptides involved in host defense systems. Apart from exerting direct anti-microbial effects, cathelicidins can regulate immune responses by affecting the activity of cells playing a role in antibacterial defense. Taking into account that mast cells are critical components of host defense, the aim of this study was to determine whether rat cathelicidin-related anti-microbial peptide (rCRAMP) can influence mast cell activity. We have demonstrated that activation of fully mature rat mast cells with rCRAMP resulted in generation and release of cysteinyl leukotrienes (cysLTs). However, rCRAMP failed to induce mast cell degranulation and histamine release. We also found that rCRAMP stimulated rat mast cells to synthesize TNF, but not CXCL8. What is more, this peptide induced GM-CSF, IL-1β, CCL2 and CCL3 but not IL-33 mRNA expression in mast cells. Finally, we showed that this cathelicidin serves as potent chemoattractant for rat mast cells. rCRAMP-mediated cysLT synthesis and mast cell migration were strongly inhibited by IL-10 pre-treatment. With the use of specific inhibitors, we established that activation of PLC/A2 and ERK1/2, but not p38, was required for rCRAMP-induced mast cell stimulation, while PI3K-dependent pathway is involved in both TNF synthesis and mast cell migration. Our results suggest that cathelicidins can amplify inflammatory responses by causing mast cells accumulation and by stimulating these cells to release potent pro-inflammatory mediators.

Mouse Bone Marrow Sca-1 + CD44 + Mesenchymal Stem Cells Kill Avirulent Mycobacteria but Not Mycobacterium tuberculosis through Modulation of Cathelicidin Expression via the p38 Mitogen-Activated Protein Kinase-Dependent Pathway

“…Previously reported findings also showed that mice deficient in MyD88 and IRAK-4 are highly susceptible to Staphylococcus aureus infection and succumb to infection, demonstrating the in vivo significance of MyD88 and IRAK-4 in pathogen-induced immune responses (32,57). MAPK pathways are involved in the modulation of CRAMP expression (38). The level of p38 MAPK was increased in M. bovis BCG-infected BM-MSCs.…”

“…The MyD88-TLR interaction is known to recruit members of the IRAK family and initiates signaling through MAPK pathways (37). Moreover, previous studies showed that MAPK pathways are involved in the modulation of CRAMP expression (38). In order to identify the MAPK pathway that could be involved in the regulation of Camp expression, we checked the expression of MAPK proteins in M. bovis BCG-infected BM-MSCs.…”

Review paper Cathelicidin impact on inflammatory cells

“…Cathelicidin LL-37 promotes degranulation and preformed mediator release from human lung mast cells [ 61 ] and stimulates degranulation and Ca 2+ mobilization in immature LAD2 human mast cells [ 62 , 63 ] as well. Moreover, this peptide activates LAD2 mast cells to synthesis and releases the strong pro-inflammatory mediators such as LTC 4 and PGD 2 [ 64 ] and rat CRAMP stimulates mature mast cells to production and release cysteinyl (cys)LTs [ 65 ]. Importantly, anti-inflammatory cytokine IL-10, but not TNF, IL-6 and CCL5, strongly inhibits CRAMP-induced cysLT synthesis [ 65 ].…”

“…Moreover, this peptide activates LAD2 mast cells to synthesis and releases the strong pro-inflammatory mediators such as LTC 4 and PGD 2 [ 64 ] and rat CRAMP stimulates mature mast cells to production and release cysteinyl (cys)LTs [ 65 ]. Importantly, anti-inflammatory cytokine IL-10, but not TNF, IL-6 and CCL5, strongly inhibits CRAMP-induced cysLT synthesis [ 65 ]. Moreover, LL-37 activates mast cells to produce newly generated cytokines, including IL-2, IL-4, IL-6, IL-31, GM-CSF, and TNF, and chemokines CCL4 and CXCL8 [ 60 , 63 , 64 ].…”

Sorafenib stimulates human skin type mast cell degranulation and maturation

“…There are several signaling molecules reported to be involved in MC differentiation, including janus kinase (JAK), signal transducer and activator of transcription (STAT), Lck/Yes novel tyrosine kinase (Lyn), Spleen tyrosine kinase (Syk), linker for activation of T cell (LAT), Fyn, GRB2-associated-binding protein 2 (Gab2), Ras, Raf, and MEK [21][22][23][24][25][26][27][28][29][30][31]. These molecules play crucial roles in either PI3K or MAPK signaling [28][29][30] (Fig.…”