Enhanced susceptibility to Leishmania infection in resistant mice in the absence of immediate early response gene X-1.
Immediate early response gene X-1 (IEX-1) is a stress-inducible gene abundantly expressed in macrophages and T cells following various stimuli. To explore a potential role for IEX-1 in control of the susceptibility to Leishmania major infection, the inflammatory response during cutaneous leishmaniasis was evaluated in 129Sv/C57BL/6-resistant mice in the presence or absence of IEX-1. Null mutation of IEX-1 enhanced the susceptibility of the mice to L. major infection, and aggravated inflammatory responses in comparison with wild-type control mice. The excessive inflammation was not ascribed to a Th2-biased immune response or a defect in Th1 polarization, but rather to an elevated level of IL-17 production by both gammadelta T and CD4(+) cells, concomitant with an increase of the neutrophil recruitment early in the infection. The lack of IEX-1 also suppressed TNF-alpha production in both macrophages and T cells, resulting in a high intralesional load of parasites and delayed healing of the lesion, both of which were reversed by TNF-alpha treatment. These findings indicate the crucial role of IL-17 and TNF-alpha in determining the outcome of L. major infection beyond a balance between Th1- and Th2-mediated immune responses.
Akilov
Oleg E
OE
Department of Dermatology, Harvard Medical School, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA. oea2@pitt.edu
Ustyugova
Irina V
IV
Zhi
Liang
L
Hasan
Tayyaba
T
Wu
Mei X
MX
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D017874:Immediate-Early Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D007113:Immunity, Innate / Q000235:genetics*; D018836:Inflammation Mediators / Q000009:adverse effects / Q000502:physiology; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012720:Severity of Illness Index
C518820:IEX-1 protein, mouse; D017874:Immediate-Early Proteins; D018836:Inflammation Mediators