Are cytokine gene polymorphisms related to in vitro cytokine production profiles?
Currently, there is much interest in the genetic basis for diseases or disease manifestations and, in particular, in whether they are related to cytokine gene polymorphisms. It has become accepted to denote such single-nucleotide polymorphisms of cytokine genes by their presumed association with high or low in vitro cytokine production. In this article, we analyze the relationship between cytokine gene polymorphisms and in vitro tumor necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma), and interleukin (IL)-10 and IL-13 production, both in liver transplant recipients and in healthy volunteers. The evaluated cytokine gene polymorphisms involved TNF-A-308; TNF-d3; IFN-G+874; IL-10-1082, -819, and -592; and IL-13+2043, and -1055. For healthy volunteers, we observed a relationship between polymorphisms of TNF-d3 and IL-10-1082 with in vitro production of TNFalpha and IL-10, respectively, whereas no significant associations were found for the other tested cytokine gene polymorphisms. For liver transplant recipients, no significant relationship could be established between any of the cytokine gene polymorphisms and in vitro production of corresponding cytokines. Also, we reviewed the literature for the association between cytokine gene polymorphisms and in vitro cytokine production in various patient groups and healthy volunteers. We found that the cellular sources, from which the cytokines were released into the culture supernatant, were different between studies. They were either whole blood, isolated monocytes, or peripheral blood mononuclear cells (PBMC). Also, the in vitro incubation protocol varied to a great extent between studies. This applied for the used in vitro stimulant, the concentration of a particular stimulant, and the length of the incubation period. Moreover, the study populations were either healthy individuals or very diverse patient groups. Therefore, it was impossible to evaluate whether in vitro cytokine production profiles really can be deduced from a particular cytokine gene polymorphism. Given the inconclusive findings, we propose to set up a multicenter workshop in which the relationship between certain cytokine gene polymorphisms and in vitro cytokine production is analyzed, using an identical in vitro cell culture system and study population. Furthermore, we suggest that cytokine gene polymorphisms be described by their localization within the gene or gene-promoter, rather than by their presumed in vitro cytokine production profile, to properly evaluate the relationship between cytokine gene polymorphisms and disease manifestations.
Warlé
Michiel C
MC
Department of Surgery, Liver Transplant Research Unit, Erasmus Medical Center, Rotterdam, The Netherlands.
Farhan
Ayar
A
Metselaar
Herold J
HJ
Hop
Wim C J
WC
Perrey
Chris
C
Zondervan
Pieter E
PE
Kap
Marcel
M
Kwekkeboom
Jaap
J
Ijzermans
Jan N M
JN
Tilanus
Hugo W
HW
Pravica
Vera
V
Hutchinson
Ian V
IV
Bouma
Gerda J
GJ
D000328:Adult; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D018793:Interleukin-13 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D016207:Cytokines; D018793:Interleukin-13; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma