title: RhoB regulates the function of macrophages in the hypoxia-induced inflammatory response.
abstract: Immune cells, particularly macrophages, play critical roles in the hypoxia-induced inflammatory response. The small GTPase RhoB is usually rapidly induced by a variety of stimuli and has been described as an important regulator of cytoskeletal organization and vesicle and membrane receptor trafficking. However, it is unknown whether RhoB is involved in the hypoxia-induced inflammatory response. Here, we investigated the effect of hypoxia on the expression of RhoB and the mechanism and significance of RhoB expression in macrophages. We found that hypoxia significantly upregulated the expression of RhoB in RAW264.7 cells, mouse peritoneal macrophages, and the spleen of rats. Hypoxia-induced expression of RhoB was significantly blocked by a specific inhibitor of hypoxia-inducible factor-1α (HIF-1α), c-Jun N-terminal kinase (JNK), or extracellular-signal regulated protein kinase (ERK), indicating that hypoxia-activated HIF-1α, JNK, and ERK are involved in the upregulation of RhoB by hypoxia. Knockdown of RhoB expression not only significantly suppressed basal production of interleukin-1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) in normoxia but also more markedly decreased the hypoxia-stimulated production of these cytokines. Furthermore, we showed that RhoB increased nuclear factor-kappa B (NF-κB) activity, and the inhibition of NF-κB transcriptional activity significantly decreased the RhoB-increased mRNA levels of IL-1β, IL-6, and TNF-α. Finally, we demonstrated that RhoB enhanced cell adhesion and inhibited cell migration in normoxia and hypoxia. Taken together, these results suggest that RhoB plays an important role in the hypoxia-induced activation of macrophages and the inflammatory response.Cellular & Molecular Immunology advance online publication, 21 September 2015; doi:10.1038/cmi.2015.78.
authors.affiliation: Department of Pathophysiology, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors.forename: Gaoxiang
authors.initials: G
authors.lastname: Huang
authors.affiliation: Department of Pathophysiology, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Pathophysiology, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors.forename: Mingzhuo
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors.forename: Yiduo
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Pathophysiology, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Department of Pathophysiology, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Lu
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D015687:Cell Hypoxia; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D000067996:RAW 264.7 Cells; D051381:Rats; D013154:Spleen / Q000473:pathology; D015854:Up-Regulation; D020743:rhoB GTP-Binding Protein / Q000378:metabolism*
chemical_list: D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D016328:NF-kappa B; D020743:rhoB GTP-Binding Protein