Nitric oxide activates the expression of IRAK-M via the release of TNF-alpha in human monocytes.
The activation of interleukin receptor associated kinases (IRAK) is an important event in several inflammatory processes. However, exposing monocytes to a nitric oxide (NO) donor inhibits the activity of IRAK-1 and its molecular interaction with TNF receptor associated factor-6 (TRAF6). Despite the fact that NO is known to regulate many events in the immune and vascular system, the mechanism that underlies this inhibition remains unknown. We have recently demonstrated that IRAK-M inhibits the TLR/IRAK pathway during endotoxin tolerance and thus, we hypothesized that IRAK-M may be involved in the inhibition of IRAK-1 activity in the presence of NO. Hence, we have analyzed the expression of IRAK-M in human monocytes following exposure to a NO donor (GSNO) and we have observed that GSNO was capable of inducing IRAK-M mRNA and protein expression 8 and 20 h after stimulation, respectively. It is known that NO induces the expression of TNF-alpha in monocytes and we found that exposure to TNF-alpha induced IRAK-M mRNA expression in human monocytes within 2 h of stimulation. Furthermore, the expression of IRAK-M induced by GSNO was inhibited by the presence of a blocking antibody raised against TNF-alpha. Thus, our data indicate that stimulation of human monocytes with a NO donor results in a clear induction of IRAK-M and this is dependent on the release of TNF-alpha by this kind of cells.
Research Unit, Department of Surgical Research, La Paz Hospital, Madrid 28046, Spain.
Carlos
C
del Fresno
Lourdes
L
Gómez-García
Luis
L
Caveda
Pedro
P
Escoll
Francisco
F
Arnalich
Ruben
R
Zamora
Eduardo
E
López-Collazo
D001483:Base Sequence; D017931:DNA Primers; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases; D009000:Monocytes / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D017931:DNA Primers; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D011494:Protein Kinases; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases