Gene expression alterations of human peripheral blood monocytes induced by medium-term treatment with the TH2-cytokines interleukin-4 and -13

Chaitidis, Pavlos; O'Donnell, Valerie Bridget; Kuban, Ralf‐Jürgen; Bermúdez-Fajardo, Alexandra; Ungethuem, Ute; Kühn, Hartmut

doi:10.1016/j.cyto.2005.02.004

Cited by 63 publications

(51 citation statements)

References 43 publications

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“…Furthermore, although the antiinflammatory effects of gAcrp are completely dependent on HO-1 (17, 18), here we find that the anti-inflammatory effects of flAcrp are only partially dependent on HO-1 expression. This partial role for HO-1 is likely due to induction of HO-1 by IL-4 (36).…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanism for Adiponectin-dependent M2 Macrophage Polarization

Mandal¹,

Pratt²,

Barnes

et al. 2011

Journal of Biological Chemistry

217

107

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The anti-inflammatory effects of globular adiponectin (gAcrp) are mediated by IL-10/heme oxygenase 1 (HO-1)-dependent pathways. Although full-length (flAcrp) adiponectin also suppresses LPS-induced pro-inflammatory signaling, its signaling mechanisms are not yet understood. The aim of this study was to examine the differential mechanisms by which gAcrp and flAcrp suppress pro-inflammatory signaling in macrophages. Chronic ethanol feeding increased LPS-stimulated TNF-␣ expression by Kupffer cells, associated with a shift to an M1 macrophage polarization. Both gAcrp and flAcrp suppressed TNF-␣ expression in Kupffer cells; however, only the effect of gAcrp was dependent on IL-10. Similarly, inhibition of HO-1 activity or siRNA knockdown of HO-1 in RAW264.7 macrophages only partially attenuated the suppressive effects of flAcrp on MyD88-dependent and -independent cytokine signatures. Instead, flAcrp, acting via the adiponectin R2 receptor, potently shifted the polarization of Kupffer cells and RAW264.7 macrophages to an M2 phenotype. gAcrp, acting via the adiponectin R1 receptor, was much less effective at eliciting an M2 pattern of gene expression. M2 polarization was also partially dependent on AMPactivated kinase. flAcrp polarized RAW264.7 macrophages to an M2 phenotype in an IL-4/STAT6-dependent mechanism. flAcrp also increased the expression of genes involved in oxidative phosphorylation in RAW264.7 macrophages, similar to the effect of flAcrp on hepatocytes. In summary, these data demonstrate that gAcrp and flAcrp utilize differential signaling strategies to decrease the sensitivity of macrophages to activation by TLR4 ligands, with flAcrp utilizing an IL-4/ STAT6-dependent mechanism to shift macrophage polarization to the M2/anti-inflammatory phenotype.Resident tissue macrophages exhibit a tremendous plasticity in their response to external stimuli. In particular, the local metabolic and immune microenvironment contributes to this plasticity (1). In response to different stimuli, macrophages express distinct patterns of surface receptors and metabolic enzymes that ultimately generate the diversity of macrophage functions. Although the precise characterization of macrophage diversity is continuing to evolve, two distinct polarization states of macrophages, M1 and M2, have been characterized (1, 2). LPS and IFN␥ can promote macrophage differentiation to a "classical" or M1 phenotype (1). The M1 activation pattern is associated with tissue destruction and inflammation and is responsible for up-regulating pro-inflammatory cytokines and increasing production of reactive nitrogen species and reactive oxygen species (1). In contrast, the "alternative" or M2 activation phenotype of macrophages is induced in response to IL-4 and IL-13. M2-polarized macrophages dampen the inflammatory process by producing anti-inflammatory factors, such as IL-10 and TGF␤. M2 macrophages also up-regulate mannose receptors, such as the macrophage mannose receptor (MMR) 2 and mannose receptor, C type 2 (Mrc2c), IL-1 receptor antagonist (I...

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Section: Discussionmentioning

confidence: 99%

Molecular Mechanism for Adiponectin-dependent M2 Macrophage Polarization

Mandal¹,

Pratt²,

Barnes

et al. 2011

Journal of Biological Chemistry

217

107

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“…It is possible that the bimodal 12-HETE and 15-HETE re-sponses observed may, thus, reflect early release of intracellular stores immediately postexercise, followed by subsequent enzymatic biosynthesis during the latter stages of recovery. Notably, 15-LOX expression is low or undetectable in most cell types, but is inducibly expressed in alternatively activated macrophages (19,21,39). Delayed elevation in 15-LOX products only at 24 h postexercise is consistent with macrophages being the predominant inflammatory cell type present during the latter stages of inflammation, including Ն24 h following exercise-induced muscle injury (69).…”

Section: Discussionmentioning

confidence: 99%

Human inflammatory and resolving lipid mediator responses to resistance exercise and ibuprofen treatment

Markworth

Vella

Lingard

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

139

158

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Classical proinflammatory eicosanoids, and more recently discovered lipid mediators with anti-inflammatory and proresolving bioactivity, exert a complex role in the initiation, control, and resolution of inflammation. Using a targeted lipidomics approach, we investigated circulating lipid mediator responses to resistance exercise and treatment with the NSAID ibuprofen. Human subjects undertook a single bout of unaccustomed resistance exercise (80% of one repetition maximum) following oral ingestion of ibuprofen (400 mg) or placebo control. Venous blood was collected during early recovery (0 -3 h and 24 h postexercise), and serum lipid mediator composition was analyzed by LC-MS-based targeted lipidomics. Postexercise recovery was characterized by elevated levels of cyclooxygenase (COX)-1 and 2-derived prostanoids (TXB2, PGE2, PGD2, PGF2␣, and PGI2), lipooxygenase (5-LOX, 12-LOX, and 15-LOX)-derived hydroxyeicosatetraenoic acids (HETEs), and leukotrienes (e.g., LTB4), and epoxygenase (CYP)-derived epoxy/dihydroxy eicosatrienoic acids (EpETrEs/DiHETrEs). Additionally, we detected elevated levels of bioactive lipid mediators with anti-inflammatory and proresolving properties, including arachidonic acid-derived lipoxins (LXA4 and LXB4), and the EPA (E-series) and DHA (D-series)-derived resolvins (RvD1 and RvE1), and protectins (PD1 isomer 10S, 17S-diHDoHE). Ibuprofen treatment blocked exercise-induced increases in COX-1 and COX-2-derived prostanoids but also resulted in off-target reductions in leukotriene biosynthesis, and a diminished proresolving lipid mediator response. CYP pathway product metabolism was also altered by ibuprofen treatment, as indicated by elevated postexercise serum 5,6-DiHETrE and 8,9-DiHETrE only in those receiving ibuprofen. These findings characterize the blood inflammatory lipid mediator response to unaccustomed resistance exercise in humans and show that acute proinflammatory signals are mechanistically linked to the induction of a biological active inflammatory resolution program, regulated by proresolving lipid mediators during postexercise recovery. eicosanoid; exercise; inflammation; nonsteroidal anti-inflammatory drug; resolution LIPID MEDIATORS ARE A DIVERSE class of bioactive autocrine/ paracrine signaling molecules that are synthesized endogenously from essential omega-6 and omega-3 fatty acids. Oxidation of free fatty acid substrates via cyclooxygenase (COX-1 and COX-2), lipoxygenase (5-LOX, 12-LOX, and 15-LOX), epoxygenase (CYP), and nonenzymatic pathways, produces a potential array of more than 100 distinct lipid mediators. Bioactive lipid mediators are involved in a wide range of physiological and pathological processes, one of the best characterized of which is their key role in the inflammatory response (reviewed in Ref. 91). Classical eicosanoids derived from omega-6 arachidonic acid (AA, -6 20:4), including prostaglandins (PGs; synthesized via COX-1 and COX-2) and leukotrienes (LTs, synthesized via 5-LOX), are well established proinflammatory signaling molecules that stimul...

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“…Although it is difficult to establish a consensus set of markers for alternative activation of monocytes/macrophages in humans, genes that are regulated by IL-4 and IL-13 include mannose receptor (MR) (36,44), Alox 15 (encodes 12/15-lipoxygenase) (3,4,47), MAO-A (46,47), CD36 (36,44,45), and FN1 (44, 47) among others. Our results demonstrate the important role of Hck in modulating the expression of the MR, a well established, universal marker of alternative activation.…”

Section: Discussionmentioning

confidence: 99%

“…Using the same Hck-specific antisense ODN, we further checked whether Hck had any effect in regulation of other markers of alternative activation like CD36 (36,44,45) or MAO-A (2,46,47). Our quantitative real-time PCR experiment data showed that the levels of both CD36 and MAO-A mRNA are up-regulated after IL-13 stimulation (Fig.…”

Section: Hck Regulates Il-13 Induction Of P38 Mapk Activation and 15-mentioning

confidence: 99%

Hck Is a Key Regulator of Gene Expression in Alternatively Activated Human Monocytes

Bhattacharjee

Pal

Cathcart

2011

Journal of Biological Chemistry

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Background: IL-13 promotes alternative activation (M2 polarization) in monocytes. Results: IL-13 induces activation of Src family kinase Hck, which is required for M2 gene expression, including 15-lipoxygenase. Conclusion: Hck acts as a key regulator controlling gene expression in alternatively activated monocytes/macrophages. Significance: A potential new role of Src family kinase Hck in M2 polarization of monocytes/macrophages.

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Gene expression alterations of human peripheral blood monocytes induced by medium-term treatment with the TH2-cytokines interleukin-4 and -13

Cited by 63 publications

References 43 publications

Molecular Mechanism for Adiponectin-dependent M2 Macrophage Polarization

Molecular Mechanism for Adiponectin-dependent M2 Macrophage Polarization

Human inflammatory and resolving lipid mediator responses to resistance exercise and ibuprofen treatment

Hck Is a Key Regulator of Gene Expression in Alternatively Activated Human Monocytes

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