Enhanced expression of intracellular heme oxygenase-1 in deactivated monocytes from patients with severe systemic inflammatory response syndrome.
BACKGROUND
Monocyte deactivation is an important contributor to infectious susceptibility in critically ill patients. However, the mechanism of monocyte deactivation has not been fully elucidated. Recently, intracellular heme oxygenese-1 (HO-1), an anti-inflammatory heat-shock protein, was reported to be activated by Toll-like receptors (TLRs), and to inhibit inflammatory cytokine production such as that of TNF-alpha. In the present study, we evaluated the expression of intracellular HO-1 and TLRs in monocytes from patients with severe systemic inflammatory response syndrome (SIRS) and examined the role of HO-1 in monocyte deactivation.


METHODS
Twenty-seven patients who fulfilled the criteria for severe SIRS and had a serum C-reactive protein (CRP) level >10 mg/dL were included in this study. The cause of SIRS was sepsis in 16 patients, trauma in 7, and other in 4. Expression of intracellular HO-1, surface TLR2 and TLR4, and intracellular cytokines (TNF-alpha, Interleukin-6) stimulated via TLR activation were measured in circulating monocytes by flow cytometry. Intracellular HO-1 expression was evaluated in normal monocytes stimulated with patient serum. Serum cytokine levels were also measured. Patient data were compared with data from healthy volunteers (n = 16).


RESULTS
Cytoplasmic HO-1 was clearly detected by fluorescence microscopy. Expression of HO-1, TLR2, and TLR4 in monocytes was significantly enhanced in patients with severe SIRS compared with that in healthy volunteers, whereas intracellular TNF-alpha expression with peptidoglycan was significantly decreased (p < 0.05) in patients compared with that in healthy volunteers. HO-1 expression was significantly enhanced in normal monocytes stimulated with patient serum. Intracellular HO-1 levels were positively related to serum TNF-alpha levels in patients (r = 0.46).


CONCLUSIONS
Expression of intracellular HO-1 and of TLRs was enhanced in deactivated monocytes from patients with SIRS. Increased production of intracellular HO-1 in response to serum factors may play a role in monocyte deactivation after systemic inflammation.
Mohri
Tomoyoshi
T
Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medical, Osaka, Japan. mouri@hp-emerg.med.osaka-u.ac.jp
Ogura
Hiroshi
H
Koh
Taichin
T
Fujita
Kieko
K
Sumi
Yuka
Y
Yoshiya
Kazuhisa
K
Matsushima
Asako
A
Hosotsubo
Hideo
H
Kuwagata
Yasuyuki
Y
Tanaka
Hiroshi
H
Shimazu
Takeshi
T
Sugimoto
Hisashi
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002097:C-Reactive Protein / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D015601:Injury Severity Score; D007378:Interleukins / Q000378:metabolism*; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D007378:Interleukins; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D051547:Heme Oxygenase-1