Leishmania promastigotes evade interleukin 12 (IL-12) induction by macrophages and stimulate a broad range of cytokines from CD4+ T cells during initiation of infection

• Published in: The Journal of experimental medicine Vol. 179; no. 2; pp. 447 - 456
• Main Authors: REINER, S. L, SHICHUN ZHENG, ZHI-EN WANG, STOWRING, L, LOCKSKEY, R. M
• Format: Journal Article
• Language: English
• Published: New York, NY Rockefeller University Press 01.02.1994; The Rockefeller University Press
• Subjects: Animals; Base Sequence; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; Cell Line; Cytokines - biosynthesis; DNA Primers; Fundamental and applied biological sciences. Psychology; Interleukin-12; Interleukin-4 - biosynthesis; Interleukins - biosynthesis; Invertebrates; Leishmania major - growth & development; Leishmania major - immunology; Leishmaniasis, Cutaneous - immunology; Leishmaniasis, Cutaneous - microbiology; Life cycle. Host-agent relationship. Pathogenesis; Macrophages - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Molecular Sequence Data; Polymerase Chain Reaction; Protozoa; RNA, Messenger - genetics; Transcription, Genetic; Protozoa; Host parasite relation; Cytokine; Rodentia; Helper cell; Interleukin 12; Cellular immunity; In vitro; Vertebrata; Mammalia; Messenger RNA; Mouse; T-Lymphocyte; Rhizoflagellata; Infected cell; Leishmania major; Macrophage
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.179.2.447

Leishmania major are intramacrophage parasites whose eradication requires the induction of T helper 1 (Th1) effector cells capable of activating macrophages to a microbicidal state. Interleukin 12 (IL-12) has been recently identified as a macrophage-derived cytokine capable of mediating Th1 effector cell development, and of markedly enhancing interferon gamma (IFN-gamma) production by T cells and natural killer cells. Infection of macrophages in vitro by promastigotes of L. major caused no induction of IL-12 p40 transcripts, whereas stimulation using heat-killed Listeria or bacterial lipopolysaccharide induced readily detectable IL-12 mRNA. Using a competitor construct to quantitate a number of transcripts, a kinetic analysis of cytokine induction during the first few days of infection by L. major was performed. All strains of mice examined, including susceptible BALB/c and resistant C57BL/6, B10.D2, and C3H/HeN, had the appearance of a CD4+ population in the draining lymph nodes that contained transcripts for IL-2, IL-4, and IFN-gamma (and in some cases, IL-10) that peaked 4 d after infection. In resistant mice, the transcripts for IL-2, IL-4, and IL-10 were subsequently downregulated, whereas in susceptible BALB/c mice, these transcripts were only slightly decreased, and IL-4 continued to be reexpressed at high levels. IL-12 transcripts were first detected in vivo by 7 d after infection, consistent with induction by intracellular amastigotes. Challenge of macrophages in vitro confirmed that amastigotes, in contrast to promastigotes, induced IL-12 p40 mRNA. Reexamination of the cytokine mRNA at 4 d revealed expression of IL-13 in all strains analyzed, suggesting that IL-2 and IL-13 may mediate the IL-12-independent production of IFN-gamma during the first days after infection. Leishmania have evolved to avoid inducing IL-12 from host macrophages during transmission from the insect vector, and cause a striking induction of mRNAs for IL-2, IL-4, IL-10, and IL-13 in CD4+ T cells. Each of these activities may favor survival of the organism.