Synergistic IL-10 induction by LPS and the ceramide-1-phosphate analog PCERA-1 is mediated by the cAMP and p38 MAP kinase pathways

Goldsmith, Meir; Avni, Dorit; Ernst, Orna; Glucksam, Yifat; Levy‐Rimler, Galit; Meijler, Michaël M.; Zor, Tsaffrir

doi:10.1016/j.molimm.2009.03.009

Cited by 31 publications

(35 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…33 There is a global phosphorylation increase in the Injury compared with the Sham group (Figure 2a), which is in line with the notion that inflammatory and/or ischemic insults activate PKA/PKC signaling. [34][35][36] Importantly, we detected a further increase in phosphorylation in the Injury+sPIF compared with the Injury group, suggesting possible modulation of PKA/PKC signaling by sPIF. 35 Thus, we reasoned that sPIF might enhance the phosphorylation of neuroprotective PKA/PKC substrates and therefore decided to test the phosphorylation status of BADSer112, GAP-43Ser41 and CREBSer133.…”

mentioning

confidence: 62%

“…The divergent in vivo effects of sPIF (neuroprotection, Figure 1) and LPS-induced neuroinflammation 24 suggest association/synergism with distinct cofactors of TLR4 signaling. 35 Thus, it is conceivable that cofactors of sPIF likely act in concert to elicit/synergize downstream effects that are specific to sPIF but different from those induced by LPS. In addition, studies to determine in vivo effects of TLR4 silencing will be needed to firmly establish the role of TLR4 in sPIF-mediated neuroprotection.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

et al. 2015

View full text Add to dashboard Cite

A synthetic peptide (sPIF) analogous to the mammalian embryo-derived PreImplantation Factor (PIF) enables neuroprotection in rodent models of experimental autoimmune encephalomyelitis and perinatal brain injury. The protective effects have been attributed, in part, to sPIF's ability to inhibit the biogenesis of microRNA let-7, which is released from injured cells during central nervous system (CNS) damage and induces neuronal death. Here, we uncover another novel mechanism of sPIF-mediated neuroprotection. Using a clinically relevant rat newborn brain injury model, we demonstrate that sPIF, when subcutaneously administrated, is able to reduce cell death, reverse neuronal loss and restore proper cortical architecture. We show, both in vivo and in vitro, that sPIF activates cyclic AMP dependent protein kinase (PKA) and calcium-dependent protein kinase (PKC) signaling, leading to increased phosphorylation of major neuroprotective substrates GAP-43, BAD and CREB. Phosphorylated CREB in turn facilitates expression of Gap43, Bdnf and Bcl2 known to have important roles in regulating neuronal growth, survival and remodeling. As is the case in sPIF-mediated let-7 repression, we provide evidence that sPIF-mediated PKA/PKC activation is dependent on TLR4 expression. Thus, we propose that sPIF imparts neuroprotection via multiple mechanisms at multiple levels downstream of TLR4. Given the recent FDA fast-track approval of sPIF for clinical trials, its potential clinical application for treating other CNS diseases can be envisioned.

show abstract

mentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

et al. 2015

View full text Add to dashboard Cite

show abstract

“…The mechanism describing how the IL-10 gene is activated in Mo-M with a proinflammatory phenotype has been under intense investigation. One explanation is that a nonclassical NF-kB activity (p50-or p52-homodimer formation) induces IL-10 transcription together with certain transcription factors (e.g., cAMP-induced CREB activity) (39). Wnt5a induces cAMP and CREB activa- tion (40).…”

Section: Discussionmentioning

confidence: 99%

Wnt5a Induces a Tolerogenic Phenotype of Macrophages in Sepsis and Breast Cancer Patients

Bergenfelz

Medrek

Ekström

et al. 2012

The Journal of Immunology

108

101

View full text Add to dashboard Cite

A well-orchestrated inflammatory reaction involves the induction of effector functions and, at a later stage, an active downregulation of this potentially harmful process. In this study we show that under proinflammatory conditions the noncanonical Wnt protein, Wnt5a, induces immunosuppressive macrophages. The suppressive phenotype induced by Wnt5a is associated with induction of IL-10 and inhibition of the classical TLR4-NF-κB signaling. Interestingly, this phenotype closely resembles that observed in reprogrammed monocytes in sepsis patients. The Wnt5a-induced feedback inhibition is active both during in vitro LPS stimulation of macrophages and in patients with sepsis caused by LPS-containing, Gram-negative bacteria. Furthermore, using breast cancer patient tissue microarrays, we find a strong correlation between the expression of Wnt5a in malignant epithelial cells and the frequency of CD163+ anti-inflammatory tumor-associated macrophages. In conclusion, our data point out Wnt5a as a potential target for an efficient therapeutic modality in severe human diseases as diverse as sepsis and malignancy.

show abstract

“…Incubation of RAW264.7 macrophages with PCERA-1 leads to a rapid increase in intra-cellular cAMP level (Goldsmith et al, 2008) and subsequent phosphorylation of CREB (Avni and Zor, unpublished). Moreover, a PKA inhibitor blocked the effect of PCERA-1 on IL-10 ( Goldsmith et al, 2009) and TNF (Avni and Zor, unpublished) production. PCERA-1 also increases phosphorylation, and hence activation, of p38 MAP kinase, both in resting macrophages and in LPS-stimulated macrophages .…”

Section: The Receptor-mediated Activities Of Pcera-1mentioning

confidence: 97%

Distinct receptor-mediated activities in macrophages for natural ceramide-1-phosphate (C1P) and for phospho-ceramide analogue-1 (PCERA-1)

Levi

Meijler

Gómez-Muñoz

et al. 2010

Molecular and Cellular Endocrinology

Self Cite

View full text Add to dashboard Cite

. Distinct receptor-mediated activities in macrophages for natural ceramide-1-phosphate (C1P) and for phospho-ceramide analogue-1 (PCERA-1). Molecular and Cellular Endocrinology, Elsevier, 2009, 314 (2) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 Ceramide-1-phosphate (C1P) is known as a second messenger regulating a multitude of processes including cell growth, apoptosis and inflammation. Exciting recent findings now suggest that C1P can stimulate macrophages migration in an extra-cellular manner via a G protein-coupled receptor (GPCR). Interestingly, a synthetic C1P analog, named phospho-ceramide analogue-1 (PCERA-1), was recently described as a potent in-vivo anti-inflammatory agent, and was suggested to act on macrophages in an extra-cellular manner via a GPCR. Here we summarize and compare the receptor-mediated as well as receptor-independent activities of natural C1P and its synthetic analog. We also provide experimental data in support of distinct C1P and PCERA-1 receptors.Page 3 of 20A c c e p t e d M a n u s c r i p t 3 IntroductionIt is well-established that sphingolipids are crucial metabolites for controlling cell and tissue homeostasis. In particular, ceramides induce cell cycle arrest and are potent inducers of apoptosis. Also, ceramides play crucial roles in the regulation of cell differentiation, and inflammation (Hannun et al., 1986;Hannun, 1994;Hannun and Obeid, 1995;Hannun, 1996;Hannun and Obeid, 2002;Kolesnick, 1994;Kolesnick, 1987;Kolesnick and Hemer, 1990;Kolesnick et al., 2000;Merrill and Jones, 1990;Merrill et al., 1997;Merrill, 2002;Spiegel and Merrill, 1996).Ceramides are generated either by de novo synthesis, or by the action of different sphingomyelinases (SMases), whose activities, enzymology, and compartmentalization have been thoroughly reviewed by others (Cremesti et al., 2002;Goni and Alonso, 2002;Kolesnick et al., 2000). A major metabolite of ceramide is ceramide-1-phosphate (C1P, Fig. 1), which is generated through direct phosphorylation of ceramide by ceramide kinase (CERK) (Bajjalieh et al., 1989;Kolesnick and Hemer, 1990). This enzyme was first shown to be confined to the microsomal fraction, but its location in the cytosol has also been reported (Mitsutake et al., 2004). Recently, Chalfant and co-workers demonstrated that CERK utilizes ceramide transported to the trans-Golgi apparatus by the ceramide transport protein (CERT). Of note, down-regulation of CERT by RNA interference resulted in strong inhibition of newly synthesized C1P, suggesting that CERT plays a critical role in C1P formation . However, this observation contrasts with that of Bornancin and...

show abstract

Synergistic IL-10 induction by LPS and the ceramide-1-phosphate analog PCERA-1 is mediated by the cAMP and p38 MAP kinase pathways

Cited by 31 publications

References 52 publications

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

Wnt5a Induces a Tolerogenic Phenotype of Macrophages in Sepsis and Breast Cancer Patients

Distinct receptor-mediated activities in macrophages for natural ceramide-1-phosphate (C1P) and for phospho-ceramide analogue-1 (PCERA-1)

Contact Info

Product

Resources

About