Abstract
Surfactant protein D (SP-D), an innate immune molecule, has an indispensable role in host defense and regulation of inflammation. Immune related functions regulated by SP-D include agglutination of pathogens, phagocytosis, oxidative burst, antigen presentation, T lymphocyte proliferation, cytokine secretion, induction of apoptosis and clearance of apoptotic cells. The present study unravels a novel ability of SP-D to reduce the viability of leukemic cells (eosinophilic leukemic cell line, AML14.3D10; acute myeloid leukemia cell line, THP-1; acute lymphoid leukemia cell lines, Jurkat, Raji; and human breast epithelial cell line, MCF-7), and explains the underlying mechanisms. SP-D and a recombinant fragment of human SP-D (rhSP-D) induced G2/M phase cell cycle arrest, and dose and time-dependent apoptosis in the AML14.3D10 eosinophilic leukemia cell line. Levels of various apoptotic markers viz. activated p53, cleaved caspase-9 and PARP, along with G2/M checkpoints (p21 and Tyr15 phosphorylation of cdc2) showed significant increase in these cells. We further attempted to elucidate the underlying mechanisms of rhSP-D induced apoptosis using proteomic analysis. This approach identified large scale molecular changes initiated by SP-D in a human cell for the first time. Among others, the proteomics analysis highlighted a decreased expression of survival related proteins such as HMGA1, overexpression of proteins to protect the cells from oxidative burst, while a drastic decrease in mitochondrial antioxidant defense system. rhSP-D mediated enhanced oxidative burst in AML14.3D10 cells was confirmed, while antioxidant, N-acetyl-L-cysteine, abrogated the rhSP-D induced apoptosis. The rhSP-D mediated reduced viability was specific to the cancer cell lines and viability of human PBMCs from healthy controls was not affected. The study suggests involvement of SP-D in host’s immunosurveillance and therapeutic potential of rhSP-D in the eosinophilic leukemia and cancers of other origins.
Highlights
Recent studies show that particular immune cell types, effector molecules, and pathways collectively form a functional cancer immunosurveillance process that detects and eliminates developing tumors [1]
For the first time, the ability of recombinant fragment of human SP-D (rhSP-D) to selectively reduce the survival of cancerous cells-AML14.3D10, Jurkat, Raji, MCF-7 and THP-1, while survival of healthy peripheral blood mononuclear cells (PBMCs) was unaltered
In the presence of rhSP-D, AML14.3D10 eosinophilic leukemia cells showed a significant increase in the number of annexin-V positive cells, G2 phase and DNA fragmentation suggesting induction of G2/M arrest and apoptosis
Summary
Recent studies show that particular immune cell types, effector molecules, and pathways collectively form a functional cancer immunosurveillance process that detects and eliminates developing tumors [1]. The present study reports for the first time, another secreted pattern recognition molecule of innate immune system, Surfactant protein D (SP-D) that exerts antileukemic properties. SP-D, a member of collectin family, is composed of N-terminal collagen region and C-terminal C-type lectin domain or carbohydrate recognition domain (CRD) region [2]. It appears to perform a crucial role in linking innate and adaptive immunity [3]. Increasing the levels of SP-D in murine models of allergy has been reported to regulate the immune cell activation, pulmonary homeostasis and resistance to allergenic challenge [5,9]. Eosinophils from healthy donors, when primed with IL-5, exhibited an increase in apoptosis following incubation with SP-D suggesting that the healthy eosinophils in the absence of priming or activation do not undergo SP-D induced apoptosis [8]
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