Mycobacterium leprae actively modulates the cytokine response in naive human monocytes.
Leprosy is a chronic but treatable infectious disease caused by the intracellular pathogen Mycobacterium leprae. Host immunity to M. leprae determines the diversity of clinical manifestations seen in patients, from tuberculoid leprosy with robust production of Th1-type cytokines to lepromatous disease, characterized by elevated levels of Th2-type cytokines and a suboptimal proinflammatory response. Previous reports have indicated that M. leprae is a poor activator of macrophages and dendritic cells in vitro. To understand whether M. leprae fails to elicit an optimal Th1 immune response or actively interferes with its induction, we have examined the early interactions between M. leprae and monocytes from healthy human donors. We found that, in naïve monocytes, M. leprae induced high levels of the negative regulatory molecules MCP-1 and interleukin-1 (IL-1) receptor antagonist (IL-1Ra), while suppressing IL-6 production through phosphoinositide-3 kinase (PI3K)-dependent mechanisms. In addition, low levels of proinflammatory cytokines were observed in association with reduced activation of nuclear factor-kappaB (NF-kappaB) and delayed activation of IL-1beta-converting enzyme, ICE (caspase-1), in monocytes stimulated with M. leprae compared with Mycobacterium bovis BCG stimulation. Interestingly, although in itself a weak stimulator of cytokines, M. leprae primed the cells for increased production of tumor necrosis factor alpha and IL-10 in response to a strongly inducing secondary stimulus. Taken together, our results suggest that M. leprae plays an active role to control the release of cytokines from monocytes by providing both positive and negative regulatory signals via multiple signaling pathways involving PI3K, NF-kappaB, and caspase-1.
Sinsimer
Daniel
D
Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute Center, International Center for Public Health, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
Fallows
Dorothy
D
Peixoto
Blas
B
Krahenbuhl
James
J
Kaplan
Gilla
G
Manca
Claudia
C
D002478:Cells, Cultured; D016207:Cytokines / Q000145:classification / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D009163:Mycobacterium bovis; D009166:Mycobacterium leprae / Q000502:physiology*; D053473:Nod2 Signaling Adaptor Protein / Q000819:agonists; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists
D016207:Cytokines; D008070:Lipopolysaccharides; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D051193:Toll-Like Receptors; D019869:Phosphatidylinositol 3-Kinases