TY - JOUR
T1 - IL6 -174 G/C promoter polymorphism influences susceptibility to mucosal but not localized cutaneous leishmaniasis in Brazil
AU - Castellucci, L.
AU - Menezes, E.
AU - Oliveira, J.
AU - Magalhaes, A.
AU - Guimaraes, L.H.
AU - Lessa, M.
AU - Ribeiro, S.
AU - Reale, J.
AU - Noronha, E.F.
AU - Wilson, M.E.
AU - Duggal, P.
AU - Beaty, T.H.
AU - Jeronimo, S.
AU - Jamieson, S.E.
AU - Bales, A.
AU - Blackwell, Jenefer
AU - De Jesus, A.R.
AU - Carvalho, E.M.
PY - 2006
Y1 - 2006
N2 - BackgroundMucosal leishmaniasis (ML) is associated with exaggerated tumor necrosis factor–α and interferon-γ responses and tissue destruction. ML follows localized cutaneous leishmaniasis (CL) caused by Leishmania braziliensis infection. Interleukin (IL)–6 down-regulates T helper (Th) cell type 1 differentiation and drives Th2 cell differentiation. The IL6 −174 G/C polymorphism is associated with proinflammatory diseases and IL-6 regulation MethodsThe −174 G/C polymorphism was genotyped in population samples and families with CL and ML from Brazil. Genotype frequencies were compared among patients with ML, patients with CL, and 2 control groups by logistic regression and family-based association test (FBAT) analysis. IL-6 levels were measured in macrophages ResultsThe C allele was more common in patients with ML than in patients with CL (odds ratio [OR], 2.55 [95% confidence interval {CI}, 1.32–4.91]; P=.005), than in patients who were leishmanin skin-test positive (OR, 2.23 [95% CI, 1.23–4.05]; P=.009), and than in neighborhood control subjects (OR, 2.47 [95% CI, 1.24–4.90]; P=.01). FBAT analysis confirmed an association between allele C and ML under both additive (z=4.295; P=.000017) and dominant (z=4.325; P=.000015) models. Significantly lower levels of IL-6 were measured in unstimulated macrophages from CC individuals than from GG individuals (P=.003) as well as after stimulation with soluble leishmania antigen (P=.009) ConclusionsIL-6 may regulate type 1 proinflammatory responses, putting individuals with low macrophage IL-6 levels at increased risk for ML.
AB - BackgroundMucosal leishmaniasis (ML) is associated with exaggerated tumor necrosis factor–α and interferon-γ responses and tissue destruction. ML follows localized cutaneous leishmaniasis (CL) caused by Leishmania braziliensis infection. Interleukin (IL)–6 down-regulates T helper (Th) cell type 1 differentiation and drives Th2 cell differentiation. The IL6 −174 G/C polymorphism is associated with proinflammatory diseases and IL-6 regulation MethodsThe −174 G/C polymorphism was genotyped in population samples and families with CL and ML from Brazil. Genotype frequencies were compared among patients with ML, patients with CL, and 2 control groups by logistic regression and family-based association test (FBAT) analysis. IL-6 levels were measured in macrophages ResultsThe C allele was more common in patients with ML than in patients with CL (odds ratio [OR], 2.55 [95% confidence interval {CI}, 1.32–4.91]; P=.005), than in patients who were leishmanin skin-test positive (OR, 2.23 [95% CI, 1.23–4.05]; P=.009), and than in neighborhood control subjects (OR, 2.47 [95% CI, 1.24–4.90]; P=.01). FBAT analysis confirmed an association between allele C and ML under both additive (z=4.295; P=.000017) and dominant (z=4.325; P=.000015) models. Significantly lower levels of IL-6 were measured in unstimulated macrophages from CC individuals than from GG individuals (P=.003) as well as after stimulation with soluble leishmania antigen (P=.009) ConclusionsIL-6 may regulate type 1 proinflammatory responses, putting individuals with low macrophage IL-6 levels at increased risk for ML.
U2 - 10.1086/505504
DO - 10.1086/505504
M3 - Article
SN - 0022-1899
VL - 194
SP - 519
EP - 527
JO - Journal Infectious Diseases
JF - Journal Infectious Diseases
IS - 4
ER -