Hypoxia-inducible factor-1alpha suppresses the expression of macrophage scavenger receptor 1.
Macrophages are distributed in all peripheral tissues and play a critical role in the first line of the innate immune defenses against bacterial infection by phagocytosis of bacterial pathogens through the macrophage scavenger receptor 1 (MSR1). Within tissues, the partial pressure of oxygen (pO2) decreases depending on the distance of cells from the closest O2-supplying blood vessel. However, it is not clear how the expression of MSR1 in macrophages is regulated by low pO2. On the other hand, hypoxia-inducible factor (HIF)-1alpha is well known to control hypoxic responses through regulation of hypoxia-inducible genes. Therefore, we investigated the effects of hypoxia and HIF-1alpha on MSR1 expression and function in the macrophage cell line RAW264. Exposure to 1% O2 or treatment with the hypoxia-mimetic agent cobalt chloride (CoCl2) significantly suppressed the expression of MSR1 mRNA, accompanied by a markedly increase in levels of nuclear HIF-1alpha protein. The overexpression of HIF-1alpha in RAW264 cells suppressed the expression of MSR1 mRNA and protein, transcriptional activity of the MSR1 gene, and phagocytic capacity against the Gram-positive bacteria Listeria monocytogenes. The suppression of MSR1 mRNA by hypoxia or CoCl2 was inhibited by YC-1, an inhibitor of HIF-1alpha, or by the depletion of HIF-1alpha expression by small interference RNA. These results indicate that hypoxia transcriptionally suppresses MSR1 expression through HIF-1alpha.
Shirato
Ken
K
Department of Molecular Predictive Medicine and Sport Science, School of Medicine, Kyorin University, 6-20-6, Shinkawa, Mitaka, Tokyo, 181-8611, Japan.
Kizaki
Takako
T
Sakurai
Takuya
T
Ogasawara
Jun-Etsu
JE
Ishibashi
Yoshinaga
Y
Iijima
Takehiko
T
Okada
Chikako
C
Noguchi
Izumi
I
Imaizumi
Kazuhiko
K
Taniguchi
Naoyuki
N
Ohno
Hideki
H
D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D003035:Cobalt / Q000494:pharmacology; D015870:Gene Expression; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010100:Oxygen; D010313:Partial Pressure; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051117:Scavenger Receptors, Class A / Q000096:biosynthesis*; D014162:Transfection
D016587:Antimutagenic Agents; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C495140:Msr1 protein, mouse; D012333:RNA, Messenger; D051117:Scavenger Receptors, Class A; D003035:Cobalt; C018021:cobaltous chloride; D010100:Oxygen