Influence of interleukin-8 (IL-8) and IL-8 receptors on the migration of human keratinocytes, the role of PLC-γ and potential clinical implications

Abstract

Abstract. Interleukin (IL)-8 is a pro-inflammatory cytokine that has a direct effect on immune cells, including polymorphonuclear cells. Keratinocytes are a rich source of IL-8. However, there is little knowledge on the role of IL-8 in clinical wound healing and the direct biological effect of IL-8 on keratinocytes. In this study, the effect of recombinant human IL-8 (rhIL-8) on migration and adhesion was tested using HaCaT keratinocytes as a cell model. The cell functions were evaluated using impedance cell sensing. The expression of IL-8 receptor (IL-8R) transcripts in human skin and wounds (acute and chronic) was assessed using real-time transcript analysis. rhIL-8 significantly increased the migration of keratinocytes (3.5±0.3 for cells treated with IL-8 vs. 2.7±0.6 for controls; p= 0.029). It is interesting to note that treatment of keratinocytes with IL-8 resulted in a marked shift in the responsive frequencies. IL-8 only resulted in a marginal increase in cell adhesion, which was particularly noticeable at high frequencies. The PLC-γ inhibitor completely eradicated the action of IL-8 on the migration of HaCaT cells. Using real time PCR, it was found that chronic wounds had significantly lower levels of the B form of the IL-8R (IL-8RB) (p=0.045) and marginally lower levels of the A form, IL-8RA, in comparison with acute wounds. Therefore, IL-8 has a direct and profound stimulatory effect on the migration of human keratinocytes, which is likely to occur via the PLC-γ pathway. Together with a reduced level of IL-8Rs in difficult-healing wounds, IL-8 has a clear prognostic and therapeutic value in wound healing.

Chemokine Regulation of Angiogenesis During Wound Healing

“…Chemokines under investigation for the treatment of chronic wound are CCL2, CXCL8, and CXCL12. [43][44][45] Because of the multifaceted function of CXCL12, that includes its ability to promote angiogenesis and reepithelialization, recruit EPC, and reduces tissue scarring, it is a potential target for the treatment of dermal wounds. 43,[46][47][48] It has been shown that direct application or lentiviral induction of CXCL12 enhances wound healing in diabetic mice.…”

Plasma interleukin-8 levels are persistently elevated for 1�month after minimally invasive colorectal resection for colorectal cancer

“…IL-8 also plays a role in and is a marker of tumor progression and metastatic disease for a wide range of cancers including gliomas as well as breast and prostate cancers (23)(24)(25). Finally, IL-8 is prominent in keratinocytes after IHC staining; this presence suggests that it is a cell migration and chemotactic factor for keratinocytes, suggesting that IL-8 plays a role in wound healing (26,27). The effect of minimally invasive colon resection (MICR) on postoperative (postop) plasma IL-8 levels is unknown.…”

Plasma Cytokine and Growth Factor Profiling during Free Flap Transplantation

“…which are associated with epithelialization [44]. IL8 has a profound effect on the migration of keratinocytes which is again critical to wound epithelialization [45]. In vitro experiments on the effect of recombinant human IL8 on keratinocyte proliferation revealed a rise in cell numbers, whereas in vivo topically applied IL8 on human skin grafts in a chimeric mouse model enhanced re-epithelialization due to elevated numbers of mitotic keratinocytes [46].…”