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IL-4 administration exerts preventive effects via suppression of underlying inflammation and TNF-α-induced apoptosis
1Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Unlabelled:
Macrophages play an important role during the development of steroid-induced osteonecrosis. Interleukin (IL)-4 administration helped reduce the infiltration of M1 phenotypic macrophages and maintain the activation of M2 phenotypic macrophages, resulting in restriction of inflammation and decrease in osteocyte apoptosis. The results indicated the therapeutic potential of IL-4 in prevention of steroid-induced osteonecrosis.
Introduction:
Steroid-induced osteonecrosis (ON) is a debilitating disease characterized by the activation and infiltration of macrophages into the necrotic site. This study aimed to investigate the effects of IL-4 administration on macrophage polarization and the involved signaling pathways.
Methods:
Fifty-six BALB/c mice were randomly divided into two groups, group M (model group) and group MI (treatment group), each containing 28 mice. ON model was induced by the injection of methylprednisolone (MPS). The mice in group MI received intra-abdominal injections of 2 μg/100 g/day of rIL-4 for five consecutive days, following the administration of MPS. Osteonecrosis was verified by histopathological staining. The expression of tumor necrosis factor-alpha (TNF-α) was analyzed by ELISA and immunohistochemistry. The infiltration of M1/M2 macrophages was examined by the expression of specific makers of F4/80, CD11c, and CD206 protein. Cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and the apoptotic signal molecules such as STAT1 and caspase-3 were examined.
Results:
Histopathological observations indicated that IL-4 administration reduced the incidence of ON and the accumulation of osteoclasts. IL-4 administration inhibited the expression of TNF-α and reduced the infiltration of M1 phenotypic macrophages and maintained relatively high level of M2 phenotypic macrophages. Additionally, TUNEL assay suggested that IL-4 intervention could reduce the number of apoptotic cells in the necrotic zone. The anti-apoptotic mechanisms were related to STAT1 phosphorylation and the activation of caspase-3.
Conclusions:
Il-4 administration could alleviate steroid associated ON in mice by inhibiting the inflammatory response, the infiltration of M1 phenotypic macrophages, and suppressing TNF-a-induced osteocytic apoptosis by inhibiting the STAT1-caspase-3 signal pathway.
Insights
Interleukin-4 (IL-4) therapy effectively combats steroid-induced osteonecrosis in mice by modulating macrophage polarization and reducing osteocyte apoptosis. This approach shows promise for preventing this debilitating bone disease.
Area of Science:
- Immunology
- Orthopedics
- Molecular Biology
Background:
- Steroid-induced osteonecrosis (ON) is characterized by macrophage infiltration into necrotic bone sites.
- Understanding macrophage polarization is crucial for developing effective ON treatments.
Purpose of the Study:
- To investigate the therapeutic effects of Interleukin-4 (IL-4) on macrophage polarization in steroid-induced ON.
- To elucidate the signaling pathways involved in IL-4's protective mechanisms.
Main Methods:
- Steroid-induced ON model established in BALB/c mice using methylprednisolone (MPS).
- Treatment group received daily rIL-4 injections for five days post-MPS administration.
- Analysis included histopathology, ELISA, immunohistochemistry, TUNEL assay, and assessment of STAT1 and caspase-3 signaling.
Main Results:
- IL-4 administration reduced ON incidence, osteoclast accumulation, and TNF-α expression.
- IL-4 shifted macrophage phenotype from M1 to M2, decreasing inflammation.
- IL-4 significantly reduced osteocyte apoptosis via the STAT1-caspase-3 pathway.
Conclusions:
- IL-4 alleviates steroid-associated ON by inhibiting inflammation and M1 macrophage infiltration.
- IL-4 suppresses TNF-α-induced osteocyte apoptosis through the STAT1-caspase-3 signaling pathway.
- IL-4 demonstrates therapeutic potential for preventing steroid-induced osteonecrosis.
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