Exogenous interleukin-12 (IL-12) exacerbates Cryptosporidium parvum infection in gamma interferon knockout mice.
Experimental infection of BALB/c- or C57BL/6-gamma-interferon-knockout (GKO) mice with Cryptosporidium parvum results in infection in both strains with different outcomes of disease. The BALB/c-GKO mice recover from infection, whereas the C57BL/6-GKO mice succumb to infection in less than 2 weeks. Differences in cytokine mRNA expression suggested that recovery may involve other cytokines. To determine whether the addition of either a Th1 or Th2 cytokine could alter the outcome of infection, we treated GKO mice with either recombinant (r)IL-4 or rIL-12 1 day before infection (DBI) or daily. No effect on the oocyst shedding patterns in either strain nor an increase in survival of the C57BL/6-GKO mice was observed in the rIL-4-treated mice. Whereas one dose of 0.5 microg rIL-12 given 1 DBI had no effect on oocyst shedding, we found that daily doses of rIL-12 administered intraperitoneally exacerbated C. parvum infection in both animal models. Administration of rIL-12 shortened the survival time in the C57BL/6-GKO mice and prevented BALB/c-GKO mice from recovering from infection. Specific proliferation of T cells to cryptosporidial antigen and Th1 and Th2 mRNA cytokine expression was markedly decreased in rIL-12-treated mice. Nitric oxide (NO) may have played a minor role in the decreased proliferation observed since levels of NO present in the splenocyte cultures from rIL-12-treated mice in response to parasite antigen stimulation were higher than those observed in controls. Thus, we propose that resistance to and recovery from C. parvum infections involves a fine balance in the amount and timing of Th1 and Th2 cytokines.
Smith
L M
LM
Department of Pediatrics, Emory University, Atlanta, Georgia 30033, USA.
Bonafonte
M T
MT
Campbell
L D
LD
Mead
J R
JR
D000818:Animals; D003457:Cryptosporidiosis / Q000188:drug therapy* / Q000276:immunology; D016785:Cryptosporidium parvum / Q000187:drug effects* / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics*; D018664:Interleukin-12 / Q000494:pharmacology* / Q000627:therapeutic use; D015847:Interleukin-4 / Q000494:pharmacology / Q000627:therapeutic use; D007422:Intestines / Q000469:parasitology / Q000473:pathology; D008099:Liver / Q000469:parasitology / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D016207:Cytokines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma