Interleukin-12 family cytokines and sarcoidosis.

Sabine Ringkowski,Cristan Herbert,Paul S. Thomas

doi:10.3389/fphar.2014.00233

Abstract

Sarcoidosis is a systemic granulomatous disease predominantly affecting the lungs. It is believed to be caused by exposure to pathogenic antigens in genetically susceptible individuals but the causative antigen has not been identified. The formation of non-caseating granulomas at sites of ongoing inflammation is the key feature of the disease. Other aspects of the pathogenesis are peripheral T-cell anergy and disease progression to fibrosis. Many T-cell-associated cytokines have been implicated in the immunopathogenesis of sarcoidosis, but it is becoming apparent that IL-12 cytokine family members including IL-12, IL-23, IL-27, and IL-35 are also involved. Although the members of this unique cytokine family are heterodimers of similar subunits, their biological functions are very diverse. Whilst IL-23 and IL-12 are pro-inflammatory regulators of Th1 and Th17 responses, IL-27 is bidirectional for inflammation and the most recent family member IL-35 is inhibitory. This review will discuss the current understanding of etiology and immunopathogenesis of sarcoidosis with a specific focus on the bidirectional impact of IL-12 family cytokines on the pathogenesis of sarcoidosis.

Highlights

The term sarcoidosis was first used in 1899 to describe pathological features of skin lesions, but is currently used to describe a systemic granulomatous inflammatory disease predominantly affecting the lungs (Boeck, 1899; Müller-Quernheim et al, 2012)
IL-27 promotes IL-10 – producing regulatory type 1 T-cells (Treg1) and can directly suppress Th17 cells (Apetoh et al, 2010; Sweeney et al, 2011; Fitzgerald et al, 2013). These results suggest a bidirectional function of IL-27, and while it seems to induce a pro-inflammatory response in naïve cells, the opposite is the case in activated cells (Kalliolias and Ivashkiv, 2008; Fitzgerald et al, 2013)
Sarcoidosis was initially believed to be a Th1/IL-12/IFNγ mediated disease, more recent advances have revealed a contribution of pro-inflammatory IL-23 and Th17 cells in granuloma formation

Summary

Introduction

The term sarcoidosis was first used in 1899 to describe pathological features of skin lesions, but is currently used to describe a systemic granulomatous inflammatory disease predominantly affecting the lungs (Boeck, 1899; Müller-Quernheim et al, 2012). The non-caseating granulomas observed in affected tissues remain its key pathological feature (Heinle and Chang, 2014). Current investigations into the pathogenesis include studies of gene polymorphisms and the role of possible infective and non-infective antigens (Adrianto et al, 2012; Negi et al, 2012; Dubaniewicz et al, 2013). Important questions that remain unexplained are how and why granulomas are formed and why approximately 20% of all patients develop pulmonary fibrosis whereas the majority experience remission (Iannuzzi and Fontana, 2011; Müller-Quernheim et al, 2012; Broos et al, 2013; Loke et al, 2013). To be explained is the observed anergy of peripheral T-cells in affected patients (Lee et al, 2011)

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