An article on pathology of Psoriasis

My today's blog is a a brief summary of a very interesting article on pathology of psoriasis by Dr Jensen and team, University of Pennsylvania School of Medicine, Philadelphia, USA.

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

Psoriasis is a noncontagious and chronic skin condition that nearly affects 0.3 to 3% of world population. Prevalence of psoriasis varies widely depending up on the ethnicity. Psoriasis occurs most commonly in Caucasians. The disease is characterized by disfigured red thickened skin covered with white/silvery scales. The management is generally done using anti-inflammatory agents such as corticosteroids and biologics such as TNF-alpha neutralizing Etanercept.
The cause of psoriasis is unknown and there is no cure. Several hypotheses have been proposed to find the cause of psoriasis. Based on these, the cause appears to be a multifactorial process which involves both genes and the environment leading to the dysregulated skin structure and chronic inflammation. Keratinocytes which are the primary constituents of the epidermis, hyper-proliferate and fail to undergo differentiation in affected skin.
Previous studies have revealed that a vast array of genes including cytokines, growth factors and differentiation markers is differentially regulated during the disease. New studies have demonstrated that activation of keratinocytes is sufficient to trigger psoriasis like lesions in transgenic mice. This process is however, dependent up on the presence of T cells demonstrating the interplay between keratinocytes and T cells. Recent reports have also suggested the role of IL-1 in the pathology of psoriasis.

There are two forms of IL-1, IL-1alpha and IL-1beta, which are encoded by separate genes. Both the IL-1alpha and IL-1beta bind to the IL-1 receptor type 1 (IL-1RI). Together with IL-1RI accessory protein (IL-1RIAcP), IL-1RI activates intracellular signaling cascades leading to activation of the transcription factors AP-1 and NF-kappaB. These transcription factors play important roles in signal transduction pathways and they regulate expression of many genes and gene products e.g., complement factors and cytokines.

After binding of the ligand to the IL-1R, IL-1R associated kinase-1 (IRAK1), a serine-threonine kinase, is recruited to the intracellular domain of IL1-RI. After activation, it gets disassociated from the receptors and activates down stream signaling factors, which in turn regulate activation of NF-kappaB. The role of IRAK1 in activation of transcription factors, AP-1 is controversial.

Il-1 has been shown to be expressed in psoriatic skin lesions. Recent studies using functional genomics have suggested that transcriptome profile derived from psoriatic skin lesions were similar to those of IL-1 stimulated keratinocytes. Thus, IL-1 has been implicated in the psoriasis associated hyper-proliferation of keratinocytes. As recent studies have suggested links between activated keratinocytes and T cells and also shown the involvement of IL-1 in psoriasis, the authors searched for potential role of Il-1 in linking keratinocytes to T cell.

The involvement of IRAK1 in IL-1 signaling in keratinocytes and the potential role that elevated IRAK1 levels may have in psoriasis pathology have never been explored. In this study, the authors have demonstrated that IL-1 stimulated keratinocytes express elevated levels of Cys-Cys (CC) and Cys-X-Cys (CXC) motif chemokines, which are involved in T cell recruitment.

The Cys-Cys chemokine (or beta-chemokine) have two adjacent cysteines, near their amino terminus. There are at least 27 distinct members of this subgroup reported for mammals, called CC chemokine ligands (CCL)-1 to -28. In case of , Cys-X-Cys chemokines (or α-chemokines), the amino terminal cysteines are separated by one amino acid, called X. There are 17 different types in mammals.

The authors also observed that while IL-1 regulated CC chemokine production was IRAK1 dependent, IL-1 and IFN-gamma regulated CXC production was IRAK-1 independent.
The major results of the study are as follows:
1. IL-1 alpha and beta stimulated keratinocytes express T cell targeting CC chemokine (CCL5 and CCl20) mRNAs present in psoriatic lesions
2. IL-1 alpha and beta up-regulates CC chemokine secretion (CCL5 and CCl20) by keratinocytes
3. IL-1beta up-regulates CXC chemokine mRNA levels but does not lead to protein secretion
4. IL-1beta amplifies chemokine production induced by INF-γ and TNF-α
5. Elevated IRAK1 levels enhance chemokine expression
6. IL-1 induced CC chemokine expression is dependent upon IRAK1
7. IL-1 effect on IFN-gamma induced CXC chemokine expression is IRAK1 independent

Reference: Sanmiguel JC, Olaru F, Li J, Mohr E, Jensen LE. Interleukin-1 regulates keratinocyte expression of T cell targeting chemokines through interleukin-1 receptor associated kinase-1 (IRAK1) dependent and independent pathways. Cell Signal. 2009 May;21(5):685-94.