ALOX12 is a gene encoding arachidonate 12-lipoxygenase (12-LOX), a
member of a non-heme lipoxygenase family of dioxygenases. ALOX12
catalyzes the addition of oxygen onto arachidonic acid producing
12-hydroperoxyeicosatetraenoic acid, 12-HPETE, which can be reduced to
eicosanoid, 12-HETE. 12-HETE acts in diverse cellular processes
including catecholamine synthesis, vasoconstriction, neuronal function
and inflammation. Consistent with effects on these fundamental
mechanisms, allelic variants of ALOX12 are associated with diseases
including schizophrenia, atherosclerosis and cancers without definition
of mechanisms. Toxoplasma gondii is an apicomplexan parasite that causes
morbidity and mortality and stimulates an innate and adaptive immune
inflammatory reaction. Recently, it has been shown that a gene region
known as Toxo1 is critical for susceptibility or resistance to T. gondii
infection in rats. An orthologous gene region with ALOX12 centromeric
is also present in humans. Herein, we report that the human ALOX12 gene
has susceptibility alleles for human congenital toxoplasmosis (rs6502997
[P<0.000309], rs312462 [P<0.028499], rs6502998 [P<0.029794],
rs434473 [P<0.038516]). A human monocytic cell line was genetically
engineered using lentivirus RNA interference to knockdown ALOX12. In
ALOX12 knockdown cells, ALOX12 RNA expression decreased and ALOX12
substrate, arachidonic acid, increased. ALOX12 knockdown attenuated
progression of T. gondii infection and resulted in greater parasite
burden, but decreased consequent late cell death of the human monocytic
cell line. These findings suggest that, ALOX12 influences host responses
to T. gondii infection in human cells. ALOX12 has been shown in other
studies to be important in numerous diseases. Herein, we now demonstrate
the critical role ALOX12 plays in T. gondii infection in humans.
member of a non-heme lipoxygenase family of dioxygenases. ALOX12
catalyzes the addition of oxygen onto arachidonic acid producing
12-hydroperoxyeicosatetraenoic acid, 12-HPETE, which can be reduced to
eicosanoid, 12-HETE. 12-HETE acts in diverse cellular processes
including catecholamine synthesis, vasoconstriction, neuronal function
and inflammation. Consistent with effects on these fundamental
mechanisms, allelic variants of ALOX12 are associated with diseases
including schizophrenia, atherosclerosis and cancers without definition
of mechanisms. Toxoplasma gondii is an apicomplexan parasite that causes
morbidity and mortality and stimulates an innate and adaptive immune
inflammatory reaction. Recently, it has been shown that a gene region
known as Toxo1 is critical for susceptibility or resistance to T. gondii
infection in rats. An orthologous gene region with ALOX12 centromeric
is also present in humans. Herein, we report that the human ALOX12 gene
has susceptibility alleles for human congenital toxoplasmosis (rs6502997
[P<0.000309], rs312462 [P<0.028499], rs6502998 [P<0.029794],
rs434473 [P<0.038516]). A human monocytic cell line was genetically
engineered using lentivirus RNA interference to knockdown ALOX12. In
ALOX12 knockdown cells, ALOX12 RNA expression decreased and ALOX12
substrate, arachidonic acid, increased. ALOX12 knockdown attenuated
progression of T. gondii infection and resulted in greater parasite
burden, but decreased consequent late cell death of the human monocytic
cell line. These findings suggest that, ALOX12 influences host responses
to T. gondii infection in human cells. ALOX12 has been shown in other
studies to be important in numerous diseases. Herein, we now demonstrate
the critical role ALOX12 plays in T. gondii infection in humans.
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