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FASEB J. 2014 Aug;28(8):3456-67. doi: 10.1096/fj.14-251306. Epub 2014 Apr 15.

Cathelicidin LL-37 induces time-resolved release of LTB4 and TXA2 by human macrophages and triggers eicosanoid generation in vivo.

Author information

1
Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry 2.
2
Institute for Cardiovascular Prevention, Ludwig Maximilians University, Munich, Germany; Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands; and German Centre for Cardiovascular Research (DZHK), Munich Heart Alliance, Munich, Germany.
3
Department of Physiology and Pharmacology, and.
4
Department of Medical Biochemistry and Biophysics, Division of Molecular Neurobiology, Karolinska Institutet, Stockholm, Sweden;
5
Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry 2, jesper.haeggstrom@ki.se.

Abstract

In humans, LL-37 and eicosanoids are important mediators of inflammation and immune responses. Here we report that LL-37 promotes leukotriene B4 (LTB4) and thromboxane A2 (TXA2) generation by human monocyte-derived macrophages (HMDMs). LL-37 evokes calcium mobilization apparently via the P2X7 receptor (P2X7R), activation of ERK1/2 and p38 MAPKs, as well as cytosolic phospholipase A2 (cPLA2) and 5-lipoxygenase in HMDMs, leading to an early (1 h) release of LTB4. Similarly, TXA2 production at an early time involved the same signaling sequence along an LL-37-P2X7R-cPLA2-cyclooxygenase-1 (COX-1) axis. However, at later (6-8 h) time points, internalized LL-37 up-regulates COX-2 expression, promoting TXA2 production. Furthermore, intraperitoneal injection of mice with murine cathelicidin-related antimicrobial peptide (mCRAMP) induces significantly higher levels of LTB4 and TXA2 in mouse ascites rich in macrophages. Conversely, cathelicidin-deficient (Cnlp(-/-)) mice produce much less LTB4 and TXB2 in vivo in response to TNF-α compared with control mice. We conclude that LL-37 elicits a biphasic release of eicosanoids in macrophages with early, Ca(2+)-dependent formation of LTB4 and TXA2 followed by a late peak of TXA2, generated via induction of COX-2 by internalized LL-37, thus allowing eicosanoid production in a temporally controlled manner. Moreover, our findings provide evidence that LL-37 is an endogenous regulator of eicosanoid-dependent inflammatory responses in vivo.

KEYWORDS:

P2X7R; antimicrobial peptides; inflammation; leukotriene; thromboxane

PMID:
24736410
DOI:
10.1096/fj.14-251306
[Indexed for MEDLINE]

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