Pleiotropic Effects of Corticotropin Releasing Hormone on Normal Human Skin Keratinocytes

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis is the major stress response system. Several components of the HPA axis, such as corticotropin-releasing hormone (CRH) and POMC peptides and their receptors are also present in the skin. In earlier studies, we showed that CRH inhibits cellular proliferation of immortalized human keratinocytes. We now examine further the functional activity of the HPA axis in the skin, by characterizing the actions of CRH on normal foreskin keratinocytes. The CRH receptor was detected as CRH-R1 antigen at 47 kDa in the cultured keratinocytes by Western blotting, and immunohistochemistry demonstrated its presence in the epidermal and follicular keratinocytes. CRH is also biologically active in cultured keratinocytes, where it inhibits proliferation and enhances the interferon-gamma-stimulated expression of the hCAM and ICAM-1 adhesion molecules and of the HLA-DR antigen. These effects were concentration-dependent, with maximal activity at CRH 10(-7) M. Thus, in the keratinocyte, the most important cellular component of the epidermis, CRH appears to induce a shift in energy metabolism away from proliferation activity, and toward the enhancement of immunoactivity. Therefore, similar to its central actions, cutaneous CRH may also he involved in the stress response, but at a highly localized level.

Corticotropin-releasing hormone stimulates NF-kappaB in human epidermal keratinocytes

“…NF-B dimers containing p65 are generally considered to stimulate gene expression (Li & Verma 2002). This data is consistent with reported enhancement of HLA-DR and ICAM-1 expression in human primary keratinocytes and inhibition of proliferation of these cells (Quevedo et al 2001). HLA-DR and ICAM-1 genes possess B binding sites (Li & Verma 2002).…”

“…Human keratinocytes express several isoforms of CRH receptor type 1 (CRH-R1) . CRH inhibits proliferation of both human primary and immortalized keratinocytes (Quevedo et al 2001, Slominski et al 2000a. CRH increases cyclic adenosine monophosphate (cAMP) production levels in immortalized keratinocytes (Slominski et al 2000a) and calcium levels in both immortalized and human primary keratinocytes (Fazal et al 1998, Slominski et al 1999, Wiesner et al 2002.…”

“…CRH increases cyclic adenosine monophosphate (cAMP) production levels in immortalized keratinocytes (Slominski et al 2000a) and calcium levels in both immortalized and human primary keratinocytes (Fazal et al 1998, Slominski et al 1999, Wiesner et al 2002. CRH increases production of IL-6 and IL-11 in immortalized keratinocytes and increases both human leukocyte antigen DR (HLA-DR) and intercellular adhesion molecule 1 (ICAM-1) expression in human primary keratinocytes (Quevedo et al 2001, Zbytek et al 2002.…”

Differential expression of HPA axis homolog in the skin

“…UV radiation and factors raising intracellular cAMP increase CRH-R1α expression and change the pattern of isoform expression Slominski et al, 2001). CRH-R1 participates in the regulation of skin cell proliferation, apoptosis, differentiation and immune activities (Carlson et al, 2001;Quevedo et al, 2001;Slominski, 2005;Slominski et al, 2000d;Slominski et al, 2006b;Zbytek et al, 2004;Zbytek and Slominski, 2005).…”

Psoriasis and Stress – Psoriasis Aspect of Psychoneuroendocrinology

“…Therefore, activation of the stress system, via the direct and indirect effects of CRH, might affect the susceptibility of an individual to certain autoimmune, allergic, infectious, inflammatory or neoplastic diseases (Arbiser et al, 1999). The biological effects of CRH have been shown to include the inhibition of keratinocyte proliferation and regulation of adhesion molecules and cytokines (cSlominski et al, 2000) (Quevedo et al, 2001) (Zbytek et al, 2002). Dysregulation of the HPA and SAM systems has been proposed as one possible underlying cause of stress-induced flares of psoriasis (Heller et al, 2011).…”