Pneumocystisstimulates MCP-1 production by alveolar epithelial cells through a JNK-dependent mechanism

Abstract

Pneumocystis carinii is an opportunistic fungal pathogen that causes pneumonia (PCP) in immunocompromised individuals. Recent studies have demonstrated that the host's immune response is clearly responsible for the majority of the pathophysiological changes associated with PCP. P. carinii interacts closely with alveolar epithelial cells (AECs); however, the nature and pathological consequences of the epithelial response remain poorly defined. Monocyte chemotactic protein-1 (MCP-1) is involved in lung inflammation, immunity, and epithelial repair and is upregulated during PCP. To determine whether AECs are an important source of MCP-1 in the P. carinii-infected lung, in vivo and in vitro studies were performed. In situ hybridization showed that MCP-1 mRNA was localized to cells with morphological characteristics of AECs in the lungs of infected mice. In vitro studies demonstrated that P. carinii stimulated a time-and dose-dependent MCP-1 response in primary murine type II cells that was preceded by JNK activation. Pharmacological inhibition of JNK nearly abolished P. carinii-stimulated MCP-1 production, while ERK, p38 MAPK, and TNF receptor signaling were not required. Furthermore, delivery of a JNK inhibitory peptide specifically to pulmonary epithelial cells using a recombinant adenovirus vector blocked the early lung MCP-1 response following intratracheal instillation of infectious P. carinii. JNK inhibition did not affect P. carinii-stimulated production of macrophage inflammatory protein-2 in vitro or in vivo, indicating that multiple signaling pathways are activated in P. carinii-stimulated AECs. These data demonstrate that AECs respond to P. carinii in a proinflammatory manner that may contribute to the generation of immune-mediated lung injury. inflammation; epithelial; AIDS PNEUMONIA INDUCED by Pneumocystis carinii (PCP) continues to be the most common AIDS-defining illness as well as an important cause of morbidity and mortality in patients with a wide array of immunosuppressive conditions. Most recent studies indicate that, although the presence of P. carinii is obviously a factor in the development of lung injury, pulmonary inflammation is a major determinant of the severity of PCP (5,27,53,54). In AIDS patients with profound reductions in CD4 ϩ T cell numbers, bronchoalveolar lavage (BAL) fluid IL-8 and neutrophil concentrations, but not organism numbers, correlate with severity of PCP (5, 23, 28). In addition, clinical studies of immune-reconstituted PCP patients and controlled animal studies have both demonstrated that inflammatory mediators are released, and immune and inflammatory cells are recruited to the lung in response to P. carinii (2,25,38,39). More defined studies in mice have identified specific T cell subsets as having prominent roles in the lung injury associated with PCP (54, 57). For example, CD8 ϩ T cells are responsible for much of the PCP-associated lung injury that occurs in CD4-deficient hosts (17). Therefore, recent studies have focused on the mechanisms by which T cells accumu...

Glycosphingolipids Mediate Pneumocystis Cell Wall β-Glucan Activation of the IL-23/IL-17 Axis in Human Dendritic Cells

“…Furthermore, their marked suppressive activities may in some situations exert beneficial effects during exuberant host inflammation, including activity in suppressing TNF-a and macrophage inflammatory protein-2 (36,37). Inflammatory responses by macrophages and epithelial cells also provide important functions in Pneumocystis host defense (67,68). However, caution must be exercised, because these agents may also suppress important DC/lymphocyte-based IL-23/IL-17 responses, which are required to clear fungal infections.…”

Critical Roles of Inflammation and Apoptosis in Improved Survival in a Model of Hyperoxia-Induced Acute Lung Injury inPneumocystis murina-Infected Mice

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MCP-1/CCR2 system is involved in high glucose-induced fibronectin and type IV collagen expression in cultured mesangial cells

“…protein expression in human synovial cells via the extracellular signal-regulated kinase pathway (38), while Pneumocystis stimulated MCP-1 production by alveolar epithelial cells through a c-Jun NH 2 -amino terminal kinase-dependent mechanism (35). MCP-1 expression was also increased in proximal tubular cells and MCs by TGF-␤1 (19,23).…”