Chemokine synthesis and cellular inflammatory changes in lungs of mice bearing p40taxof human T-lymphotropic virus type 1

Abstract

SUMMARYTo elucidate the pathogenic mechanisms of human T-lymphotropic virus type 1 (HTLV-1)-associated lung inflammation, we conducted a histopathological and molecular analysis study using transgenic mice bearing pX region of this virus. In these mice, accumulations of inflammatory cells consisting mainly of lymphocytes were present in peribronchiolar and perivascular areas and alveolar septa, while control littermate mice did not show such changes. In situ hybridization showed that the anatomic distribution of p40 tax mRNA was similar to that of inflammatory cells, typically in peribronchiolar areas and to a lesser extent in perivascular and alveolar septa. Inflammatory cytokines, including IL-1b , tumour necrosis factor-alpha and interferon-gamma, and several chemokines, such as monocyte chemotactic protein-1 (MCP-1), RANTES, macrophage inflammatory protein-1a (MIP-1a ) and IP-10, were detected in lungs of transgenic mice but not control mice. Semiquantitative analysis using reverse transcription-polymerase chain reaction showed a significant correlation between MCP-1 mRNA expression and p40 tax mRNA, but not with other chemokines. The gene expression of the above chemokines, with the exception of MIP-1a , correlated with the severity of histopathological changes in the lung. Considered together, our results suggested that p40 tax synthesis may be involved in the development of lung lesions caused by HTLV-1 through the induction of local production of chemokines.

Elevated Chemokine Responses Are Maintained in Lungs after Clearance of Viral Infection

“…The types of chemokines induced in the lungs of MHV-68-infected mice confirm and extend the findings of Sarawar and colleagues (21) and are similar to those seen following infection with other respiratory viruses (7,8,14,32), suggesting a common pattern of innate immune response to viral infections of the lungs. Thus, the early expression of MIP-1␣, MIP-1␤, MIP-2, and MCP-1 may be due to release of chemokines from infected cells and may contribute to the recruitment of inflammatory cells to the site of infection.…”

“…Infection with respiratory viruses has been associated with lung inflammation and the induction of chemokines critical to the inflammatory response (7,8,10,14,32). Furthermore, induction of chemokine synthesis occurred early after infection in these studies and was postulated to be part of the innate immune response to viral infection.…”

“…Thus, the early expression of MIP-1␣, MIP-1␤, MIP-2, and MCP-1 may be due to release of chemokines from infected cells and may contribute to the recruitment of inflammatory cells to the site of infection. Most studies of chemokines induced following infection of lungs with viruses have focused on early times postinfection, when viral replication is highest (7,8,14,32). Therefore, it is unknown whether prolonged chemokine production is unique to MHV-68 infection or characteristic of other viral infections of the lungs.…”

Increased Expression of <i>HBZ</i> and <i>Foxp3</i> mRNA in Bronchoalveolar Lavage Cells Taken from Human T-lymphotropic Virus Type 1-associated Lung Disorder Patients

“…It is commonly known that tax activates cellular signaling pathways, and transactivates cellular immune responses, including those leading to cytokine production. We previously reported that there were increased mRNA expression levels of Th1 related cytokines and chemokines in the lungs of transgenic mice bearing the pX region (44), with a significant correlation between the tax mRNA expression levels and pathological inflammatory changes in the lungs of these transgenic mice (45).…”

Elevated expression of CCL5/RANTES in adult T‐cell leukemia cells: Possible transactivation of the CCL5 gene by human T‐cell leukemia virus type I tax

“…We observed induction of CCL5 both at the mRNA and protein levels in JPX-9 cells. Furthermore, Miyazato et al 53 have demonstrated elevated expression levels of CCL5 in lungs of transgenic mice and the correlation between its expression and the severity of histopathological changes in the lung. CCL5 may contribute to the accumulation of T lymphocytes in the lungs, leading to inflammation of the lungs in HTLV-I carrier.…”