The influence of gender on human innate immunity.
BACKGROUND
Several experimental, clinical, and epidemiologic studies indicate a better prognosis in women after an infectious challenge. The monocyte/macrophage, as coordinators of the innate immune response to sepsis, secrete plasma inflammatory cytokines. Elevated plasma cytokine levels are inversely correlated with outcome. In addition, single-nucleotide polymorphisms related to these cytokine genes and in genes important for lipopolysaccharide (LPS) detection, particularly toll-like receptor-4, have been associated with variations in clinical outcome. We hypothesize that the gender differences in clinical outcome are due to measurable differences in cytokine responses and intracellular signaling, and these differences are independent of polymorphism carrier status.


METHODS
Venous blood samples from healthy subjects (56 men, 23 women) were incubated with LPS, and supernatant cytokine levels were determined by enzyme-linked immunosorbent assay. In a randomly chosen subgroup, (8 men, 4 women), peripheral blood mononuclear cells were isolated, and LPS-mediated intracellular mitogen-activated protein kinase (MAPK) phosphorylation was assayed via Western blot analysis. Each subject was screened for the following SNPs: tumor necrosis factor alpha (TNF-alpha) -308G/A, interleukin (IL)-6 -174G/C, IL-1beta -31C/T, and toll-like receptor-4 (TLR4) +896A/G.


RESULTS
Women produced significantly less LPS-induced TNF-alpha and IL-1beta but not IL-6. When the analysis was adjusted for the presence of each polymorphism, the differences in TNF-alpha and IL-1beta accumulation persisted. Female gender was associated with lower MAPK phosphorylation at each LPS concentration but was not statistically significant.


CONCLUSIONS
Gender-specific differences in LPS-induced TNF-alpha and IL-1beta were observed, possibly attributed to alterations in MAPK phosphorylation. Furthermore, studies investigating the influence of genomic variation on the innate immune response should address potential gender-related differences.
Imahara
Scott D
SD
Department of Surgery, University of Washington and Harborview Medical Center, Seattle 98104, USA. imaharas@u.washington.edu
Jelacic
Sandra
S
Junker
Christopher E
CE
O'Keefe
Grant E
GE
D000328:Adult; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics; D012727:Sex Characteristics; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases