Differential monocyte/macrophage interleukin-1ß production due to biomaterial topography requires the ß2 integrin signaling pathway.

Monocytes/macrophages are crucial mediators of the host response to biomaterials, and their level of activation can be directly affected by material characteristics. Previous work has demonstrated that primary human monocytes cultured on polytetrafluoroethylene materials of varying topography but identical surface chemistry are differentially affected. Monocytes/macrophages on biaxially-expanded polytetrafluoroethylene with an average intranodal distance of 4.4 µm (4.4-ePTFE) produced higher levels of the inflammatory cytokine interleukin-1 beta (IL-1ß) compared with monocytes/macrophages on nonporous polytetrafluoroethylene (np-PTFE). The current study provides a mechanistic understanding of this response. Scanning electron microscopy revealed that monocytes/macrophages cultured on np-PTFE were more spread than those on 4.4-ePTFE. In addition, the actin cytoskeleton and intact ß2 integrin receptors were necessary for IL-1ß production by monocytes/macrophages on 4.4-ePTFE. This IL-1ß production also required the transcription factor nuclear factor kappa-B, another component of the ß2 integrin signaling pathway, although it may not be the primary transcription factor involved. These studies demonstrate the importance of several ß2 integrin signaling components to the monocyte/macrophage response to biomaterial topography.

Mechanistic analysis of macrophage response to IRAK-1 gene knockdown by a smart polymer-antisense oligonucleotide therapeutic.

An excessive inflammatory response is a clinical problem following major infections and severe injury that may lead to Sepsis Syndrome and Multiple Organ Failure (MOF), including the Acute Respiratory Distress Syndrome (ARDS). Management of excessive inflammation may be possible through control of key inflammatory pathways such as those mediated by the important interleukin-1 receptor associated kinase-1 (IRAK-1). In the current study, we report the impact on gene expression induced by lipopolysaccharide (LPS) stimulation of THP-1 cells treated with an antisense oligonucleotide (ASODN) against the IRAK-1 gene using cDNA microarrays and quantitative RT-PCR. The therapeutic ASODN was delivered using a pH-sensitive, membrane-interactive polymer that destabilizes the endosomal membrane to enhance access cytoplasmic delivery in targeted cells. Following LPS stimulation, the anti-inflammatory activity of ASODN against the IRAK-1 gene expression is evidenced by the lower expression of inflammatory chemokines, cytokines and acute-phase proteins compared to control cells. These results provide a larger mechanistic picture of IRAK-1 knockdown by this polymer therapeutic in macrophage-like cells.