Neutrophil cannibalism – a back up when the macrophage clearance system is insufficient

BACKGROUND: During a lipopolysaccharide-induced lung inflammation, a massive accumulation of neutrophils occurs, which is normally cleared by macrophage phagocytosis following neutrophil apoptosis. However, in cases of extensive apoptosis the normal clearance system may fail, resulting in extensive neutrophil secondary necrosis. The aim of this study was to explore the hypothesis that neutrophils, in areas of the lung with extensive cellular infiltration, contribute to clearance by phagocytosing apoptotic cells and/or cell debris derived from secondary necrosis. METHODS: Intranasal lipopolysaccharide administration was used to induce lung inflammation in mice. The animals were sacrificed at seven time points following administration, bronchoalveolar lavage was performed and tissue samples obtained. Electron microscopy and histochemistry was used to assess neutrophil phagocytosis. RESULTS: Electron microscopic studies revealed that phagocytosing neutrophils was common, at 24 h after LPS administration almost 50% of the total number of neutrophils contained phagosomes, and the engulfed material was mainly derived from other neutrophils. Histochemistry on bronchoalvolar lavage cells further showed phagocytosing neutrophils to be frequently occurring. CONCLUSION: Neutrophils are previously known to phagocytose invading pathogens and harmful particles. However, this study demonstrates that neutrophils are also able to engulf apoptotic neutrophils or cell debris resulting from secondary necrosis of neutrophils. Neutrophils may thereby contribute to clearance and resolution of inflammation, thus acting as a back up system in situations when the macrophage clearance system is insufficient and/or overwhelmed

Suppression of Growth by All-trans Retinoic Acid Requires Prolonged Induction of Interferon Regulatory Factor 1 in Cervical Squamous Carcinoma (SiHa) Cells

All-trans retinoic acid (ATRA) suppresses growth of cervical dysplasias in vivo, although the sensitivity to retinoids is frequently lost during cervical carcinogenesis. It has been suggested that prolonged treatment or use of higher doses of retinoids might offer favorable response rates. We found SiHa cervical squamous carcinoma cells that were virtually resistant to ATRA-induced growth-inhibitory effects at physiological doses (10(−7 to) 10(−6) M) to be more responsive at pharmacological doses (10(−5 to) 10(−4) M). The growth inhibition by high-dose (10(−4) M) ATRA was associated with a sustained activation of interferon regulatory factor 1 (IRF-1), while a low dose (10(−6) M) of ATRA activated IRF-1 only transiently. Antisense IRF-1 inhibited the high-dose (10(−4) M), ATRA-mediated growth arrest; forced expression of IRF-1 caused a significant reduction in cell growth. High-dose (10(−4) M) ATRA increased binding of NF-κB and STAT1 proteins to sequences that originated from the IRF-1 promoter region, while low-dose (10(−6) M) ATRA induced only NF-κB binding. A delayed tyrosine phosphorylation of the signal transducer and activator of transcription-1 (STAT1) was observed after high-dose (10(−4) M) but not low-dose (10(−6) M) ATRA treatment. In agreement with this, induction of IRF-1 mRNA by ATRA was only modest and transient in a STAT1 knockout cell line, suggesting the importance of STAT1 in sustained IRF-1 expression. Our data showed that ATRA is capable of inducing dose-dependent cellular changes, which might be appropriate to overcome resistance to retinoids that frequently develops during cervical carcinogenesis