Effects of soluble TNF receptor treatment on lipopolysaccharide-induced myocardial cytokine expression.
Tumor necrosis factor (TNF)-alpha plays a key role in the pathogenesis of septic shock syndrome, and myocardial TNF-alpha expression may contribute to this pathophysiology. We examined the myocardial expression of TNF-alpha-related cytokines and chemokines in mice exposed to lipopolysaccharide (LPS) and tested the effects of anti-TNF therapy on myocardial cytokine expression. Cytokine mRNA levels were measured by RNase protection assay, and protein levels in the plasma and myocardium were assessed by enzyme-linked immunosorbent assays. LPS (4 microg/g body wt ip) induced marked cytokine expression, including TNF-alpha, interleukin (IL)-1beta, IL-6, and monocyte chemotactic protein (MCP)-1, in both the plasma and myocardium. Pretreatment with adenovirus-mediated TNF receptor fusion protein (AdTNFR1; 10(9) plaque-forming units iv) decreased plasma cytokine levels. In contrast, whereas myocardial IL-1beta expression was also suppressed, expression of IL-6 and MCP-1 was not inhibited by AdTNFR1. In summary, anti-TNF treatment differentially altered the cytokine expression in the plasma and myocardium during endotoxemia. Inability to block myocardial expression of IL-6 and MCP-1 suggests a possible mechanism for the failure of anti-TNF therapies in the treatment of endotoxin shock.
Kadokami
T
T
Cardiovascular Institute of the University of Pittsburgh Medical Center Health System, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.
McTiernan
C F
CF
Kubota
T
T
Frye
C S
CS
Bounoutas
G S
GS
Robbins
P D
PD
Watkins
S C
SC
Feldman
A M
AM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000097:blood / Q000235:genetics; D016207:Cytokines / Q000097:blood / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000097:blood / Q000235:genetics; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics; D018664:Interleukin-12 / Q000097:blood / Q000235:genetics; D015850:Interleukin-6 / Q000032:analysis / Q000097:blood / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D012772:Shock, Septic / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D015703:Antigens, CD; D018932:Chemokine CCL2; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12