Increased productivity of tumor necrosis factor-alpha in helper T cells in patients with systolic heart failure.
OBJECTIVE
Whereas increased circulating proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), play an important role in heart failure, where and how TNF-alpha production is upregulated remains largely unknown. We studied the productivity of TNF-alpha in peripheral lymphocytes and underlying mechanisms in patients with heart failure.


METHODS
Symptomatic NYHA II-IV patients with chronic heart failure with systolic dysfunction (n=39, aged 74+/-11, ejection fraction [EF]<==50%) were compared with asymptomatic NYHA I patients (n=18, aged 72+/-10, EF>50%) and normal subjects (n=15, aged 67+/-11). Lymphocyte subsets (CD3, CD4, and CD8) and intracellular production of TNF-alpha in peripheral leukocytes were quantified by immunofluorescent flow cytometry, and relationships between these parameters and circulating proinflammatory cytokines were analyzed.


RESULTS
Subpopulation of TNF-alpha-producing CD4 was larger in NYHA II-IV patients (23.7% [18.0-28.6]) than in normal subjects (17.1% [6.5-19.5], p<0.05) and was correlated with plasma TNF-alpha levels (r=0.26, p<0.05), EF (r=-0.26, p<0.05), CD4/CD8 ratios (r=0.42, p<0.001), and subpopulation of TNF-alpha-producing monocytes (r=0.47, p<0.0001). Plasma levels of soluble CD14 and interleukin-12 (IL-12) were significantly higher in NYHA II-IV patients than in normal subjects (1971 ng/mL [1740-2375] vs. 1607 ng/mL [1530-1930], p<0.01; and 121 pg/mL [62-230] vs. 62 pg/mL [54-99], p<0.05, respectively), and plasma IL-12 levels were correlated with plasma TNF-alpha levels (r=0.41, p<0.001).


CONCLUSIONS
Increased productivity of TNF-alpha in helper T cells, associated with their dominance over cytotoxic T cells, may partially contribute to an increase in circulating TNF-alpha levels in heart failure.
Satoh
Shinji
S
Division of Cardiovascular and Geriatric Medicine, Kyushu University Hospital at Beppu, Beppu 874-0838, Japan. satoshin@qmed.hosp.go.jp
Oyama
Jun-Ichi
J
Suematsu
Nobuhiro
N
Kadokami
Toshiaki
T
Shimoyama
Nobuo
N
Okutsu
Masaaki
M
Inoue
Takeshi
T
Sugano
Masahiro
M
Makino
Naoki
N
D000368:Aged; D005260:Female; D005434:Flow Cytometry; D006333:Heart Failure / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018664:Interleukin-12 / Q000097:blood; D018950:Lipopolysaccharide Receptors / Q000097:blood; D016131:Lymphocyte Subsets; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000097:blood; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000276:immunology; D015854:Up-Regulation
D018950:Lipopolysaccharide Receptors; D014409:Tumor Necrosis Factor-alpha; D020097:Natriuretic Peptide, Brain; D018664:Interleukin-12