Mice with STAT6-targeted gene disruption develop a Th1 response and control cutaneous leishmaniasis.
The cutaneous growth of Leishmania mexicana was measured in STAT6-deficient mice (STAT6-/-) and compared with that in similarly infected wild-type (STAT6+/+) mice. Following s.c. inoculation with 5 x 10(6) amastigotes of L. mexicana into the shaven rump, STAT6+/+ mice developed large, nonhealing cutaneous lesions, while STAT6-/- mice failed to develop detectable lesions during most of the course of study. As infection progressed, STAT6+/+ mice infected with L. mexicana displayed significantly higher titers of Leishmania-specific IgG1 and IgE compared with STAT6-/- mice, which conversely produced significantly higher titers of Leishmania-specific IgG2a, indicating development of a Th1-like response in the latter group. At 12 wk postinfection, Leishmania Ag-stimulated lymph node cells from STAT6-/- mice produced significantly higher amounts of IL-12 and IFN-gamma than those from STAT6+/+ mice as measured by ELISA. However, there was no significant difference in IL-4 production between the two groups. Semiquantitative RT-PCR of transcript levels in intact draining lymph nodes and skin from inoculation sites confirmed a similar pattern of cytokines in vivo as that observed in stimulated lymph node cells in vitro. These results indicate that STAT6-mediated IL-4 signaling is critical for progression of L. mexicana infection in genetically susceptible mice and demonstrate that in the absence of STAT6, susceptible mice default toward a Th1-like response and control cutaneous L. mexicana infection.
Stamm
L M
LM
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Räisänen-Sokolowski
A
A
Okano
M
M
Russell
M E
ME
David
J R
JR
Satoskar
A R
AR
D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis / Q000097:blood; D000953:Antigens, Protozoan / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D017353:Gene Deletion; D018390:Gene Targeting; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D007894:Leishmania mexicana / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D050800:STAT6 Transcription Factor; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic / Q000276:immunology
D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D016207:Cytokines; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma