Lymphocyte/macrophage interactions: Biomaterial surface‐dependent cytokine, chemokine, and matrix protein production

Abstract

The role of lymphocytes in the biological response to synthetic polymers is poorly understood despite the transient appearance of lymphocytes at the biomaterial implant site. To investigate cytokines, chemokines, and extracellular matrix (ECM) proteins produced by lymphocytes and macrophages in response to biomaterial surfaces, human peripheral blood monocytes and lymphocytes were co-cultured on polyethylene terephthalate (PET)-based material surfaces displaying distinct hydrophobic, hydrophilic/neutral, hydrophilic/anionic, and hydrophilic/cationic chemistries. Antibody array screening showed the majority of detected proteins are inflammatory mediators that guide the early inflammatory phases of wound healing. Proteomic ELISA quantification and adherent cell analysis were performed after 3, 7, and 10 days of culture. IL-2 and IFN-γ were not detected in any co-cultures suggesting lack of lymphocyte activation. The hydrophilic/neutral surfaces increased IL-8 relative to the hydrophobic PET surface (p<0.05). The hydrophilic/anionic surfaces promoted increased TNF-α over hydrophobic and cationic surfaces and increased MIP-1β compared to hydrophobic surfaces (p<0.05). Since enhanced macrophage fusion was observed on hydrophilic/anionic surfaces, the production of these cytokines likely plays an important role in the fusion process. The hydrophilic/cationic surface promoted IL-10 production and increased matrix metalloproteinase (MMP)-9/tissue inhibitor of MMP (TIMP) relative to hydrophilic/neutral and anionic surfaces (p<0.05). These results suggest hydrophilic/neutral and anionic surfaces promote pro-inflammatory responses and reduced degradation of the ECM, whereas the hydrophilic/cationic surfaces induce an anti-inflammatory response and greater MMP-9/TIMP with an enhanced potential for ECM breakdown. The study also underscores the usefulness of protein arrays in assessing the role of soluble mediators in the inflammatory response to biomaterials.

Foreign body reaction to biomaterials

“…However, the production of cytokines, chemokines, and extracellular matrix proteins were biomaterial surface chemistry dependent. [145] Utilizing the in vitro co-cultures and the transwell system for isolating paracrine interactions, lymphocytes, via paracrine and juxtacrine means, enhanced adherent macrophage/FBGC activation in terms of inflammatory cytokine production (unpublished results). Therefore, our laboratory has demonstrated that both direct (juxtacrine) and indirect (paracrine) mechanisms of interactions between lymphocytes and macrophages may play an integral part in the inflammatory, foreign body reaction, and wound healing events that occur at the tissue/material interface.…”

In vitro response of human peripheral blood mononuclear cells to AISI 316L austenitic stainless steel subjected to nitriding and collagen coating treatments

“…Therefore, the production of cytokines by blood cells in biocompatibility studies has been widely investigated [40,41]. Even if Janský et al [17], who studied the dynamics of cytokine production in human PBMC, reported that many cytokines reach maximal levels after 4 or 12 or 24 h, other authors have chosen to assay cytokine production after longer times of incubation [19]. In our research, cytokine levels were determined after 48 h of culture, in order to refer the release of the cytokines to PBMC proliferation.…”

“…Also a biomaterial may induce the activation of macrophages, which, in an attempt to phagocytose it, secrete many inflammatory mediators, such as cytokines. Chang et al [19] investigated cytokines, chemokines, and extracellular matrix (ECM) proteins produced by lymphocytes and macrophages in response to biomaterial surfaces. These authors hypothesized that the production of inflammatory molecules from lymphocytes and macrophages in response to the contact with biomaterials could be modulated by the biomaterial surface chemistry.…”

Proteins as biocatalysts and biomaterials

“…These findings provided insight into lymphocyte and macrophage interactions in response to biomaterial surfaces along with evidence consistent with the hypothesis that distinct surface chemistries modulate lymphocyte and macrophage interactions. Finally, a mechanistic model which would provide a tool for further analysis of lymphocyte and macrophage interactions in response to biomaterial surfaces and a step toward quantitative predictability of biomaterialdependent processes was presented [19]. Combinatorial techniques also help in protein biomaterial design [25].…”