The regulation of cytokine production by macrophages and dendritic cells

When appropriately stimulated, macrophages  are capable of producing large quantities of proinflammatory and antiinflammatory cytokines. Often the balance between these two classes of cytokines can determine both the quality and character of the immmune responses that ensue. We have demonstrated that the ligation of Fcg receptors on both macrophages and dendritic cells can exert a profound influence on cytokine production by these cells.  On macrophages, FcgR ligation (in this case from E-IgG) results in a profound decrease in IL-12 production (top) and a dramatic increase in IL-10 secretion (bottom) in response to a variety of stimuli (Figure 1).  We have termed macrophages that are activated in the presence of immune complexes, Type II activated macrophages (Mf-II). These cells exert potent anti-inflammatory effects.  They can completely reverse lethal endotoxemia  J. Immunology 166:6861-68 and when used as APCs they can skew the adative immune response toward a Th2-like response J. Immunology. 168:3697-3701.

Current studies  focus on the regulation of IL-10 gene expression in macrophages.  The signal transduction pathways leading to IL-10 production and the mechanism of gene induction are being studied.  These studies have the potential to lead to the development of a novel class of anti-inflammatory compounds that work by inducing IL-10 production from macrophages.

Representative publications pertaining to cytokine production

Sutterwala, F.S., Noel, G.J., Salgame, P.S. and Mosser, D.M. 1998. Reversal of proinflammatory responses by ligating the macrophage FcγRI. J. Experimental Medicine 188:217-222.

Gerber, J.S. and Mosser, D.M. 2001. Reversing lipopolysdaccharide toxicity by ligating the macrophage Fc(gamma) receptors. J. Immunology 166:6861-68.

Anderson, C.A. and Mosser, D.M. 2002. Cutting Edge: Biasing immune responses by directing antigen to macrophage Fcg receptors. J. Immunology. 168:3697-3701.

Anderson, C.A. and Mosser, D.M. 2002. A novel macrophage phenotype: the Type II macrophage. J. Leukocyte Biology. 72:101-106.

Mosser, D.M. 2003. The many faces of macrophage activation. J. Leukocyte Biology. 73:209-212.

Cao, SJ., Zhang, X., Edwards, J.P., and Mosser, D.M. 2006.  NF-kappaB1 (p50) homodimer differentially regulate pro- and anti-inflammatory cytokines in macrophages.  J. Biological Chemistry. In Press.

Zhang, X., Edwards, J.P., and Mosser, D.M.. 2006. Dynamic and transient remodelling of the macrophage IL-10 promoter during ranscription. J. Immunology. 177:1282-1288.

Edwards, J.P., Zhang, X., Frauwirth, K., and Mosser, D.M.. 2006. Biochemical and Functional Characterization of Three Activated Macrophage Populations. J. Leukocyte Biol. In Press.

Studies to determine the molecular mechanisms by which receptor ligation influences cytokine production are underway. Cytokine gene expression and the transcription factors that drive gene expression are being studied (see link, below). The goal of this work is to determine whether we can reliably influence cytokine production by targeting antigen to specific cellular receptors on antigen presenting cells. 

Figure1. In situ ATPase staining of skin dendritic cells from mouse epidermis.

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Leishmania and host defense

The Mosser laboratory focuses on the interaction of macrophages with intracellular pathogens.  Protozoan parasites in the genus Leishmania spp reside in macrophage phagolysosomes (Figure to right), and cause a spectrum of diseases in tropical and subtropical regions of the world. Recent work has begun to examine the role of macrophage-derived cytokines in influencing the progression of visceral leishmaniasis. 

Other studies focus on the relationship between innate immunity and the development of an acquired immune response. These studies have shown that Leishmania enter macrophages by a quiescent mechanism that fails to induce innate cytokine production. This observation has led to a novel vaccination approach. Leishmania which have been genetically engineered to express host immune molecules are being developed. These genetically modified parasites are being used to determine the extent to which Leishmania avoids innate immunity to establish intracellular infection.

Mentink Kane, M. and Mosser, D.M. 2001. The role of IL-10 in promoting disease progression in Leishmaniasis. J. Immunology. 166:1141-47.

Darrah, P.A., Hondalus, M.K., Chen, Q., Ischiropoulos, H. and Mosser, D.M. 2000. Cooperation between Reactive Oxygen and Nitrogen Intermediates in the Killing of Rhodococcus equi by Activated Macrophages. Infection and Immunity. 68:3587-93.

Chen, G., Darrah, P.A., and Mosser, D.M. 2001. Vaccination against the intracellular pathogen, Leishmania spp by directing CD40 Ligand to macrophages. Infection and Immunity. 69:3255-63.

Miles, S.A., Conrad, S.M., Alves, R.G., Jeronimo, S.M.B., and Mosser, D.M. 2005.  A role for immune complexes during infection with the intracellular pathogen, Leishmania spp.  J. Experimental Medicine. 201:747-754.

Yang, Z., Mosser, D.M., and Zhang, X. 2007. Activation of the MAPK, ERK following Leishmania amazonensis infection of macrophages. J. Immunology. 178:1077-85.

Strauss-Ayali, D., Conrad, S.M. and Mosser, D.M. 2007. Monocyte subpopulations and their differentiation patterns during infection. J. Leukocyte Biol. 82:244-52.

Field, A.E., Wagage, S., Conrad, S.M, and Mosser, D.M. 2007. Reduced pathology following infection with transgenic Leishmania major expressing murine CD40 ligand. Infection and Immunity. 75:3140-49.

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