Selective induction of monocyte and not neutrophil-attracting chemokines after influenza A virus infection.

Abstract

SummaryIt is characteristic for virus infections that monocytes/macrophages and lymphocytes infiltrate infected tissue while neutrophils are absent. To understand the mechanisms selectively attracting mononuclear cells in viral diseases, we examined in an influenza A virus model the expression and regulation of chemokines as candidate molecules responsible for the immigration of leukocytes into inflamed tissue. After influenza A virus infection of human monocytes, a rapid expression of the mononuclear cell attracting CC-chemokine genes MIP-1 , MCP-1, and RANTES occurred which was followed by the release ofchemokine proteins. In striking contrast to CC-chemokines, the expression of the prototype neutrophil CXC-chemoattractants IL-8 and GRO-oe was completely suppressed after influenza A infection. The release of other neutrophil chemotactic factors was excluded by nficrochemotaxis assays. These results suggest that the virus-specific induction of mononuclear cell-attracting chemokines accounts for the preferential influx ofmononuclear leukocytes into virus-infected tissue.A hallmark of tissue inflammation is the recruitment, immigration and activation of leukocytes. Gradients of chemotactic factors direct transendothelial migration and movement through the extracellular matrix (1). Most viral diseases are characterized by the development of a specific infiltration consisting predominantly of mononuclear leukocytes while neutrophils are absent as long as no complicating bacterial superinfection occurs. Previous reports show that exposure of monocytes or macrophages to virus results in the release of various proinflammatory cytokines (2-5). Along this line, we demonstrated that an infection of monocytes with influenza A or coxsackie B3 virus induced TNF-o~, IL-1, and IL-6 production (6-9). However, the induction of these proinflammatory cytokines cannot explain the development of characteristic mononuclear leukocyte infiltrations in virally infected tissue.In virus infections, little attention has been focused on the chemokine family and a systematic analysis is still missing. Chemokines are potent chemoattractant cytokines (10, 11) and have to be considered as the main candidate molecules responsible for the selective recruitment of distinct leukocyte populations. Members of the CC-chemokine subfamily, such as MIP-lcl 1 (macrophage inflammatory protein-lc~), MCP-1 (monocyte chemotactic protein-I), and RANTES (regulated upon activation, normal T cell expressed and secreted) preferentially attract monocytes and lymphocytes (12). The CXC-chemokines which contain an ELR-motifpreceding the first cysteine, such as IL-8 (interleukin-8) or GRO-ci (melanoma growth stimulatory activity) are major neutrophil chemoattractants (13).As a first step to study the mechanisms responsible for the generation of a typical virus-induced tissue infiltration consisting predominantly of mononuclear cells, we employed influenza A virus to infect human monocytes. Here we report the selective induction of mononuclear cell attracting chemokine...

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