Functional Role of Kallikrein 6 in Regulating Immune Cell Survival

Kallikrein 6 (KLK6) is a newly identified member of the kallikrein family of secreted serine proteases that prior studies indicate is elevated at sites of central nervous system (CNS) inflammation and which shows regulated expression with T cell activation. Notably, KLK6 is also elevated in the serum of multiple sclerosis (MS) patients however its potential roles in immune function are unknown. Herein we specifically examine whether KLK6 alters immune cell survival and the possible mechanism by which this may occur.Using murine whole splenocyte preparations and the human Jurkat T cell line we demonstrate that KLK6 robustly supports cell survival across a range of cell death paradigms. Recombinant KLK6 was shown to significantly reduce cell death under resting conditions and in response to camptothecin, dexamethasone, staurosporine and Fas-ligand. Moreover, KLK6-over expression in Jurkat T cells was shown to generate parallel pro-survival effects. In mixed splenocyte populations the vigorous immune cell survival promoting effects of KLK6 were shown to include both T and B lymphocytes, to occur with as little as 5 minutes of treatment, and to involve up regulation of the pro-survival protein B-cell lymphoma-extra large (Bcl-XL), and inhibition of the pro-apoptotic protein Bcl-2-interacting mediator of cell death (Bim). The ability of KLK6 to promote survival of splenic T cells was also shown to be absent in cell preparations derived from PAR1 deficient mice.KLK6 promotes lymphocyte survival by a mechanism that depends in part on activation of PAR1. These findings point to a novel molecular mechanism regulating lymphocyte survival that is likely to have relevance to a range of immunological responses that depend on apoptosis for immune clearance and maintenance of homeostasis

Malignant inflammation in cutaneous T-cell lymphoma: a hostile takeover

Cutaneous T-cell lymphomas (CTCL) are characterized by the presence of chronically inflamed skin lesions containing malignant T cells. Early disease presents as limited skin patches or plaques and exhibits an indolent behavior. For many patients, the disease never progresses beyond this stage, but in approximately one third of patients, the disease becomes progressive, and the skin lesions start to expand and evolve. Eventually, overt tumors develop and the malignant T cells may disseminate to the blood, lymph nodes, bone marrow, and visceral organs, often with a fatal outcome. The transition from early indolent to progressive and advanced disease is accompanied by a significant shift in the nature of the tumor-associated inflammation. This shift does not appear to be an epiphenomenon but rather a critical step in disease progression. Emerging evidence supports that the malignant T cells take control of the inflammatory environment, suppressing cellular immunity and anti-tumor responses while promoting a chronic inflammatory milieu that fuels their own expansion. Here, we review the inflammatory changes associated with disease progression in CTCL and point to their wider relevance in other cancer contexts. We further define the term "malignant inflammation" as a pro-tumorigenic inflammatory environment orchestrated by the tumor cells and discuss some of the mechanisms driving the development of malignant inflammation in CTCL

Coal workers’ pneumoconiosis: An Australian perspective

Coal workers’ pneumoconiosis (CWP) is an untreatable but preventable lung disease arising from chronic inhalation of coal dust. Recent reports of CWP in Queensland, along with international data, suggest that there is a resurgence in pneumoconiosis. The prevalence of CWP varies considerably between countries. In Australia, there is no mandatory reporting system and no national data on the prevalence of CWP. The symptoms and manifestations of CWP vary depending on the composition of the inhaled dust, duration of exposure, stage of disease and host-related factors. CWP may develop into progressive massive fibrosis (PMF), which can be fatal. Radiological assessment should be performed according to evidence-based standards using the ILO (International Labour Office) International Classification of Radiographs of Pneumoconioses. As preventing exposure to coal dust prevents CWP, it is important to implement and enforce appropriate standards limiting exposure. In Australia, these standards currently vary between states and are not in keeping with international understanding of the levels of coal dust that cause disease. Longitudinal screening programs are crucial for monitoring the health of coal workers to identify individuals with early-stage disease and prevent progression from mild disease to PMF. We recommend: standardisation of coal dust exposure limits, with harmonisation to international regulations; implementation of a national screening program for at-risk workers, with use of standardised questionnaires, imaging and lung function testing; development of appropriate training materials to assist general practitioners in identifying pneumoconiosis; and a system of mandatory reporting of CWP to a centralised occupational lung disease register