The diverse functions of macrophages as participants in innate and acquired immune responses are regulated by the specific milieu of environmental factors, cytokines, and other signaling molecules that are encountered at sites of inflammation. Microarray analysis of the transcriptional response of mouse peritoneal macrophages to the T H 2 cytokine interleukin-4 (IL-4) identified Ym1 and arginase as the most highly up-regulated genes, exhibiting more than 68-and 88-fold induction, respectively. Molecular characterization of the Ym1 promoter in transfected epithelial and macrophage cell lines revealed the presence of multiple signal transducers and activators of transcription 6 (STAT6) response elements that function in a combinatorial manner to mediate transcriptional responses to IL-4. The participation of STAT6 as an obligate component of protein complexes binding to these sites was established by analysis of nuclear extracts derived from STAT6-deficient macrophages. Macrophage expression of Ym1 was highly induced in vivo by an IL-4-and STAT6-dependent mechanism during the evolution of allergic peritonitis, supporting the biological relevance of the IL-4-dependent pathway characterized ex vivo in peritoneal macrophages. These studies establish Ym1 as a highly inducible STAT6-dependent transcript in T H 2-biased inflammation and define Cis-active elements in the Ym1 promoter that are required for this transcriptional response.
Dectin-1 is the archetypal signaling, non-Toll-like pattern recognition receptor that plays a protective role in immune defense to Candida albicans as the major leukocyte receptor for β-glucans. Dectin-1-deficiency is associated with impaired recruitment of inflammatory leukocytes and inflammatory mediator production at the site of infection. In this study, we have used mice to define the mechanisms that regulate the dectin-1-mediated inflammatory responses. Myeloid cell activation by dectin-1 is controlled by inherent cellular programming, with distinct macrophage and dendritic cell populations responding differentially to the engagement of this receptor. The inflammatory response is further modulated by the progression of the phagocytosis, with “frustrated phagocytosis” resulting in dramatically augmented inflammatory responses. These studies demonstrate that dectin-1 in isolation is sufficient to drive a potent inflammatory response in a context-dependent manner. This has implications for the mechanism by which myeloid cells are activated during fungal infections and the processes involved in the therapeutic manipulation of the immune system via exogenous dectin-1 stimulation or blockade.
Abstract-Chemokines are important mediators of macrophage and T-cell recruitment in a number of inflammatory pathologies, and chemokines expressed in atherosclerotic lesions may play an important role in mononuclear cell recruitment and macrophage differentiation. We have analyzed the expression of the linked chromosome 16q13 genes that encode macrophage-derived chemokine (MDC/CCL22), thymus-and activation-regulated chemokine (TARC/ CCL17), and the CX 3 C chemokine fractalkine (CX 3 CL1) in primary macrophages and human atherosclerotic lesions by reverse transcription-polymerase chain reaction and immunohistochemistry. We show that macrophage expression of the chemokines MDC, fractalkine, and TARC is upregulated by treatment with the Th2-type cytokines interleukin-4 and interleukin-13. High levels of MDC, TARC, and fractalkine mRNA expression are seen in some, but not all, human arteries with advanced atherosclerotic lesions. Immunohistochemistry shows that MDC, fractalkine, and TARC are expressed by a subset of macrophages within regions of plaques that contain plaque microvessels. We conclude that MDC, fractalkine, and TARC, which are chromosome 16q13 chemokines, could play a role in mononuclear cell recruitment into atherosclerotic lesions and influence the subsequent inflammatory response. Macrophage-expressed chemokines upregulated by interleukin-4 may be useful surrogate markers for the presence of Th2-type immune responses in human atherosclerotic lesions. Key Words: chemokines Ⅲ atherosclerosis Ⅲ macrophages Ⅲ Th2-type T cells A therosclerosis is a major cause of morbidity and mortality in western countries. Atherosclerotic lesions within major blood vessels are responsible for myocardial infarction, strokes, and peripheral vascular disease. The initial event in the development of the atherosclerotic lesion is the adhesion of monocytes to the endothelial cells of the blood vessel wall and the extravasation of monocytes into the subendothelial space. 1,2 Recruited monocytes differentiate into macrophages and accumulate modified forms of LDL via scavenger receptors to yield lipid-laden foam cells. 3 Chronic recruitment of mononuclear cells into the developing lesion contributes to the growth of lesions and occlusion of the blood vessel. 4 Macrophages and T cells within atherosclerotic lesions produce an array of cytokines, growth factors, and inflammatory mediators, which are likely to play a role in continued mononuclear cell recruitment. 5,6 Chemoattractant cytokines (chemokines) are small disulfide-linked polypeptides of typically 60 to 70 amino acids in length that are potent chemoattractants for leukocytes. 7 The chemokine supergene family, which was unrecognized 10 years ago, now has Ͼ40 different members classified into different subfamilies on the basis of conserved structural features. 8,9 The CXC (or ␣) chemokines have a single amino acid separating the first 2 cysteine residues of the protein, whereas CC (or ) chemokines have no amino acid separating the signature C1 and C2 cysteines. The CC ch...
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