title: A role for leukocyte-derived IL-1RA in DC homeostasis revealed by increased susceptibility of IL-1RA-deficient mice to cutaneous leishmaniasis.
abstract: Dendritic cell (DC)-derived IL-1α/β plays a critical role in the induction of T helper type 1 (Th1)-dependent immunity against Leishmania. DCs from susceptible BALB/c mice produce less IL-1α/β when compared with resistant C57BL/6 mice, contributing to aberrant Th2 development and ultimate death of infected mice. We have extended our studies of the role of IL-1 in leishmaniasis using IL-1RA(-/-) BALB/c mice that are characterized by upregulated IL-1 receptor signaling. Unexpectedly, infection of IL-1RA(-/-) mice led to significantly worsened disease outcome with larger lesions, dramatically higher parasite burdens, and decreased IFN-γ production by antigen-specific T cells. We determined that IL-1RA(-/-) DCs were more mature already in the steady state, exhibited less phagocytotic capacity, and IL-12 production in response to various stimuli was impaired. Our data suggest that in addition to effects on Th education, IL-1α/β signaling also modulates DC homeostasis with increased signaling, leading to downmodulation of IL-12 synthesis and worsened disease outcome after infection with Leishmania major. Thus, the complex regulation of various members of the IL-1 cytokine family mediated through effects on both DCs and T cells critically contributes to disease outcome against this important human pathogen.
authors.affiliation: Department of Dermatology, Johannes-Gutenberg University, Mainz, Germany.
authors.forename: Kordula
authors.initials: K
authors.lastname: Kautz-Neu
authors.forename: Susanna Lopez
authors.initials: SL
authors.lastname: Kostka
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dinges
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Mark C
authors.initials: MC
authors.lastname: Udey
authors.forename: Esther
authors.initials: E
authors.lastname: von Stebut
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000469:parasitology; D003713:Dendritic Cells / Q000276:immunology* / Q000469:parasitology; D004198:Disease Susceptibility / Q000276:immunology; D016130:Immunophenotyping; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics* / Q000276:immunology*; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D010587:Phagocytosis / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000469:parasitology
chemical_list: C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D018664:Interleukin-12