IL-4 and IL-13 regulate the induction of indoleamine 2,3-dioxygenase activity and the control of Toxoplasma gondii replication in human fibroblasts activated with IFN-gamma.
The ability of up-regulatory [recombinant (r) IFN-gamma, rIFN-beta and rTNF-alpha] and down-regulatory (rIL-4, rIL-10 and rIL-13) cytokines to control the expression of indoleamine 2,3-dioxygenase (INDO) and anti-Toxoplasma activity in the human fibrosarcoma cell line 2C4 was evaluated. Activation of fibroblasts with rIFN-gamma, rIFN-beta and rTNF-alpha resulted in augmentation of INDO expression and activity leading to 40.0, 25.0 and 27.0 % inhibition of tachyzoite growth, respectively. An additive effect was observed when host cells were incubated with rIFN-gamma plus rTNF-alpha. With regard to the down-regulatory cytokines we observed that IL-4 as well as IL-13, but not IL-10, induced significant inhibition of IFN-gamma-induced control of parasite replication, INDO mRNA expression and tryptophan catabolism. Similarly, IL-4 but not IL-10 inhibited the cell surface expression of HLA-DR and CD2 induced by IFN-gamma. Consistent with these findings we were able to detect by reverse transcription-PCR the expression of mRNA for different chains of IL-4 and IL-13 receptors (IL-4Ralpha, IL-13Ralpha1 and IL-13Ralpha2) but not for IL-10 receptor in the 2C4 and other human lung fibroblast cell lines (LL24 and MRC5). Together our results indicate that IL-4 and IL-13, but not IL-10, are implicated in the negative regulation of IFN-gamma-induced anti-Toxoplasma activity in human cells from fibroblast lineage.
Chaves
A C
AC
Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Cerávolo
I P
IP
Gomes
J A
JA
Zani
C L
CL
Romanha
A J
AJ
Gazzinelli
R T
RT
D000818:Animals; D018801:CD2 Antigens / Q000096:biosynthesis; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D005347:Fibroblasts / Q000469:parasitology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D018793:Interleukin-13 / Q000494:pharmacology*; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D018123:Receptors, Interleukin / Q000235:genetics; D053701:Receptors, Interleukin-10; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4 / Q000235:genetics; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014122:Toxoplasma / Q000187:drug effects* / Q000502:physiology; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
D018801:CD2 Antigens; D006684:HLA-DR Antigens; C508181:IL13RA1 protein, human; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins; D015847:Interleukin-4; D007371:Interferon-gamma; D014366:Tryptophan Oxygenase