LEISHMANIA PROMASTIGOTES EVADE INTERLEUKIN 12 (IL-12) INDUCTION BY MACROPHAGES AND STIMULATE A BROAD RANGE OF CYTOKINES FROM CD4(-CELLS DURING INITIATION OF INFECTION() T)

Leishmania major are intramacrophage parasites whose eradication requi res the induction of T helper 1 (Th1) effector cells capable of activa ting macrophages to a microbicidal state. Interleukin 12 (IL-12) has b een recently identified as a macrophage-derived cytokine capable of me diating Th1 effector cell development, and of markedly enhancing inter feron gamma (IFN-gamma) production by T cells and natural killer cells . Infection of macrophages in vitro by promastigotes of L. major cause d no induction of IL-12 p40 transcripts, whereas stimulation using hea t-killed Listeria or bacteria lipopolysaccharide induced readily detec table IL-12 mRNA. Using a competitor construct to quantitate a number of transcripts, a kinetic analysis of cytokine induction during the fi rst few days of infection by L. major was performed. All strains of mi ce examined, including susceptible BALB/c and resistant C57BL/6, B10.D 2, and C3H/HeN, had the appearance of a CD4(+) population in the drain ing lymph nodes that contained transcripts for IL-2, IL-4, and IFN-gam ma (and in some cases, IL-10) that peaked 4 d after infection. In resi stant mice, the transcripts for IL-2, IL-4, and IL-10 were subsequentl y 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 aft er infection, consistent with induction by intracellular amastigotes. Challenge of macrophages in vitro confirmed that amastigotes, in contr ast to promastigotes, induced IL-12 p40 mRNA. Reexamination of the cyt okine 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 pro duction of IFN-gamma during the first days after infection. Leishmania have evolved to avoid inducing IL-12 from host macrophages during tra nsmission from the insect vector, and cause a striking induction of mR NAs for IL-2, IL-4, IL-10, and IL-13 in CD4(+) T cells. Each of these activities may favor survival of the organism.