Interleukin-1 regulates keratinocyte expression of T cell targeting chemokines through interleukin-1 receptor associated kinase-1 (IRAK1) dependent and independent pathways

Abstract

IL-1 is a potent pro-inflammatory cytokine that activates intracellular signaling cascades some of which may involve IL-1 receptor associated kinase-1 (IRAK1). Psoriasis is a T cell dependent chronic inflammatory condition of the skin of unknown cause. IL-1 has been implicated in psoriasis pathology, but the mechanism has not been elucidated. Interestingly, expression of IRAK1 is elevated in psoriatic skin. To identify a potential link between IL-1, keratinocytes and T cells in skin inflammation we employed pathway-focused microarrays to evaluate IL-1 dependent gene expression in keratinocytes. Several candidate mRNAs encoding known T cell chemoattractants were identified in primary keratinocytes and the stable keratinocyte cell line HaCaT. CCL5 and CCL20 mRNA and protein levels were confirmed up-regulated by IL-1 in concentration and time-dependent manners. Furthermore IL-1 synergized with IFN-γ and TNF-α. Expression of CXCL9, CXCL10 and CXCL11 mRNAs was also increased in response to IL-1, but protein could only be detected in medium from cells treated with IFN-γ alone or in combination with IL-1. Over-expression of IRAK1 led to increased constitutive and cytokine induced production of CCL5 and CCL20. Inhibition of IRAK1 activity through RNAi or expression of a dominant negative mutant blocked production of CCL5 and CCL20 but had no effect upon the IL-1 enhancement of IFN-γ induced CXCL9, CXCL10 and CXCL11 production. In conclusion IL-1 regulates T cell targeting chemokine production in keratinocytes through IRAK1 dependent and independent pathways. These pathways may contribute to acute and chronic skin inflammation.

Alarmin Function of Cathelicidin Antimicrobial Peptide LL37 through IL-36γ Induction in Human Epidermal Keratinocytes

“…We also showed that p38 and JNK MAPK and NF-kB signaling affected the induction of chemokines in combination with IL-36 and LL37; these results are similar to those from a previous study that demonstrated that IL-36 phosphorylates NF-kB and JNK and p38 MAPK (30). IL-1b and IL-1R-associated kinase-1 are aberrantly expressed in psoriatic lesions, and the synergy between IL-1b and TNF-a leads to sustained inflammatory responses (42). IL-18 induces IFN-g, and the increased IL-18 participates in the development of the Th1 response in lesional skin of psoriasis (43).…”

Staphylococcus aureus Stimulates Neutrophil Targeting Chemokine Expression in Keratinocytes through an Autocrine IL-1α Signaling Loop

“…Given the capability of S. aureus to colonize the skin and many infections start as abrasions of the skin we were interested in evaluating the role of human keratinocytes in recruiting neutrophils. Using microarray analyses of chemokine mRNA expression in response to IL-1 we have previously observed that mRNAs encoding the neutrophil targeting chemokines CXCL1 and CXCL2 were up-regulated by IL-1 (Sanmiguel et al , 2009). However, these observations were not further examined.…”

MicroRNA-31 Is Overexpressed in Psoriasis and Modulates Inflammatory Cytokine and Chemokine Production in Keratinocytes via Targeting Serine/Threonine Kinase 40

“…Keratinocytes in psoriasis lesions overexpress several proinflammatory cytokines and chemokines, which contribute to the maintenance of inflammation in psoriasis skin lesions and represent a crucial element in psoriasis pathogenesis (1). IL-1b is a proinflammatory cytokine, which is essential for Th17 differentiation (38) and potentiates immune cell activation by regulating T cell-targeting chemokine production in keratinocytes (39). Keratinocyte-derived CXCL1, CXCL5, and CXCL8/IL-8 can potently activate endothelial cells and are chemoattractants for multiple subsets of leukocytes, especially neutrophil granulocytes, by binding to the cognate receptors CXCR1 and CXCR2 (20).…”