title: From macrophage interleukin-13 receptor to foam cell formation: mechanisms for αMβ2 integrin interference.
abstract: IL-13 is a potent stimulator of alternative monocyte/macrophage activation. During alternative activation, the expression of several proteins is induced including 15-lipoxygenase (15-LO), a lipid-peroxidating enzyme and the scavenger receptor CD36. We previously reported that α(M)β(2) integrin activation or clustering suppresses the expression of both 15-LO and CD36. In this study we focused on exploring the molecular mechanisms that down-regulate CD36 expression and CD36-mediated foam cell formation in IL-13-stimulated monocytes/macrophages after α(M)β(2) activation. Our studies reveal that α(M)β(2) integrin activation inhibits the IL-13 activation of several critical pathways that are required for macrophage alternative activation; namely, blocking Jak2 and Tyk2 phosphorylation, which bind to the cytoplasmic tails of the IL-4Rα/IL-13Rα1 complex. This leads to the inhibition of tyrosine phosphorylation of Stats (Stat1, Stat3, and Stat6) and prevents the formation of a signaling complex (containing p38MAPK, PKCδ, and Stat3) that are critical for the expression of both 15-LO and CD36. Jak2-mediated Hck activation is also inhibited, thereby preventing Stats serine phosphorylation, which is essential for downstream Stat-dependent gene transcription. Moreover, inhibition of Jak2, Tyk2, or their downstream target 15-LO with antisense oligonucleotides profoundly inhibits IL-13-induced CD36 expression and CD36-dependent foam cell formation, whereas13(S) Hydroperoxyoctadecadienoic acid (HPODE), a 15-LO product and peroxisome proliferator-activated receptor-γ ligand, completely restores CD36 expression in monocytes treated with 15-LO antisense. α(M)β(2) integrin activation controls CD36 expression and foam cell formation in alternatively activated monocyte/macrophages by blocking Tyk2/Jak2 phosphorylation via a 15-LO-dependent pathway. The discovery of this mechanism helps our understanding of the potential role of alternatively activated macrophages in atherogenesis and highlights the impact of integrin α(M)β(2) on this process.
authors.affiliation: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Valentin P
authors.initials: VP
authors.lastname: Yakubenko
authors.forename: Linda C
authors.initials: LC
authors.lastname: Hsi
authors.forename: Martha K
authors.initials: MK
authors.lastname: Cathcart
authors.forename: Ashish
authors.initials: A
authors.lastname: Bhattacharjee
mesh_terms: D000818:Animals; D050197:Atherosclerosis; D018955:CD36 Antigens / Q000096:biosynthesis; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D005487:Foam Cells / Q000166:cytology*; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D053660:Receptors, Interleukin-13 / Q000378:metabolism*; D015398:Signal Transduction; D053634:TYK2 Kinase / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D018793:Interleukin-13; D008055:Lipids; D016177:Macrophage-1 Antigen; D053660:Receptors, Interleukin-13; D015847:Interleukin-4; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C070139:TYK2 protein, human; C499356:Tyk2 protein, mouse