Helen P. Carroll

SOCS2 regulates T helper type 2 differentiation and the generation of type 2 allergic responses

SOCS2-deficient T cells more readily produce Th2 cytokines, and SOCS2-deficient mice exhibit exacerbated atopic dermatitis and allergic airway inflammation.

Signalling, inflammation and arthritis Crossed signals: the role of interleukin-15 and -18 in autoimmunity

Several cytokines are involved in the complex processes ultimately leading to autoimmune diseases. In a preceding review, we have already discussed the role of the IL-12 and -17 families of cytokines. This review is focused on IL-15 and -18. Both these molecules have pro-inflammatory activity and act on many cell types and because of their broad spectrum of activity they play an important role in autoimmunity and disease pathogenesis. Their biological activity is ultimately regulated by the signalling cascades set into motion within their target cells. In this second review, we will, once again, describe the signal transduction pathways activated by these two cytokines and focus on how this relates to the pathogenesis of autoimmune diseases. We will also describe some of the therapeutic approaches that are being investigated to curtail the pro-inflammatory activities of these two molecules.

Siglec-E Is Up-Regulated and Phosphorylated Following Lipopolysaccharide Stimulation in Order to Limit TLR-Driven Cytokine Production

Although production of cytokines by TLR is essential for viral and bacterial clearance, overproduction can be detrimental, thus controlling these responses is essential. CD33-related sialic acid binding Ig-like lectin receptors (Siglecs) have been implicated in the control of leukocyte responses. In this study, we report that murine Siglec-E is induced by TLRs in a MyD88-specific manner, is tyrosine phosphorylated following LPS stimulation, and negatively regulates TLR responses. Specifically, we demonstrate the Siglec-E expression inhibits TLR-induced NF-κB and more importantly, the induction of the antiviral cytokines IFN-β and RANTES. Siglec-E mediates its inhibitory effects on TIR domain containing adaptor inducing IFN-β (TRIF)-dependent cytokine production via recruitment of the serine/threonine phosphatase SHP2 and subsequent inhibition of TBK1 activity as evidenced by enhanced TBK1 phosphorylation in cells following knockdown of Siglec-E expression. Taken together, our results demonstrate a novel role for Siglec-E in controlling the antiviral response to TLRs and thus helping to maintain a healthy cytokine balance following infection.

The newest interleukins: recent additions to the ever-growing cytokine family.

Cytokines play a critical role in the control of the innate and adaptive immune responses. The most recent additions to the ever-growing family of cytokines include interleukin (IL)-27, IL-28A, IL-28B, IL-29, IL-31, IL-32, and IL-33. Many of the newly identified cytokines and/or their specific receptors have been identified using bioinformatics. The coming of age of this discipline has coincided with completion of the sequencing of the human genome thus enabling the identification of new uncharacterized proteins. The latest additions to the interleukin family have shed new light on the intricacies of immune system regulation. These novel cytokines have pleiotrophic actions ranging from antiviral immunity to the regulation of Th2 immune responses. For example, the discovery of IL-27 has greatly improved our understanding of the factors regulating the polarization of the T helper cell responses and IL-31 appears to be an important regulator of Th2 responses. On the other hand, IL-28 and IL-29 are considered to be critical for mounting an efficient antiviral response and IL-32 and IL-33, which are yet to be fully characterized, are emerging as important components of the inflammatory response in allergy and autoimmunity. These new cytokine/receptor combinations may therefore serve as novel targets for the treatment and control of allergy, autoimmune diseases, and some cancers.

Signalling, inflammation and arthritis Crossed signals: the role of interleukin (IL)-12, -17, -23 and -27 in autoimmunity

Autoimmune diseases such as rheumatoid arthritis are the consequence of a persistent imbalance between pro- and anti-inflammatory immune mechanisms leading to chronic inflammation. The action of several cytokines is at the basis of this complex process. This review is focused on the signalling events triggered by two major groups of cytokines, namely the IL-12 and IL-17 families, which in the past few years have been shown to have a prominent role in the pathogenesis of such diseases. In particular, we will focus on the signalling cascades set in motion by such cytokines and how this may relate to the pathogenesis of human immune and inflammatory disorders as knowledge of such cascades may help in the development of novel therapeutic approaches for such diseases.

CCL11 blocks IL-4 and GM-CSF signaling in hematopoietic cells and hinders dendritic cell differentiation via suppressor of cytokine signaling expression

The chemokine eotaxin/CCL11 is an important mediator of leukocyte migration, but its effect on inflammatory cytokine signaling has not been explored. In this study, we find that CCL11 induces suppressor of cytokine signaling (SOCS)1 and SOCS3 expression in murine macrophages, human monocytes, and dendritic cells (DCs). We also discover that CCL11 inhibits GM‐CSF‐mediated STAT5 activation and IL‐4‐induced STAT6 activation in a range of hematopoietic cells. This blockade of cytokine signaling by CCL11 results in reduced differentiation and endocytic ability of DCs, implicating CCL11‐induced SOCS as mediators of chemotactic inflammatory control. These findings demonstrate cross‐talk between chemokine and cytokine responses, suggesting that myeloid cells tracking to the inflammatory site do not differentiate in the presence of this chemokine, revealing another role for SOCS in inflammatory regulation.

Regulation of Foxp3+ Inducible Regulatory T Cell Stability by SOCS2

Suppressor of cytokine signaling (SOCS) proteins are key regulators of CD4+ T cell differentiation, and in particular, we have recently shown that SOCS2 inhibits the development of Th2 cells and allergic immune responses. Interestingly, transcriptome analyses have identified SOCS2 as being preferentially expressed in both natural regulatory T cells (Tregs) and inducible Tregs (iTregs); however, the role of SOCS2 in Foxp3+ Treg function or development has not been fully elucidated. In this study, we show that despite having no effect on natural Treg development or function, SOCS2 is highly expressed in iTregs and required for the stable expression of Foxp3 in iTregs in vitro and in vivo. Indeed, SOCS2-deficient CD4+ T cells upregulated Foxp3 following in vitro TGF-β stimulation, but failed to maintain stable expression of Foxp3. Moreover, in vivo generation of iTregs following OVA feeding was impaired in the absence of SOCS2 and could be rescued in the presence of IL-4 neutralizing Ab. Following IL-4 stimulation, SOCS2-deficient Foxp3+ iTregs secreted elevated IFN-γ and IL-13 levels and displayed enhanced STAT6 phosphorylation. Therefore, we propose that SOCS2 regulates iTreg stability by downregulating IL-4 signaling. Moreover, SOCS2 is essential to maintain the anti-inflammatory phenotype of iTregs by preventing the secretion of proinflammatory cytokines. Collectively, these results suggest that SOCS2 may prevent IL-4–induced Foxp3+ iTreg instability. Foxp3+ iTregs are key regulators of immune responses at mucosal surfaces; therefore, this dual role of SOCS2 in both Th2 and Foxp3+ iTregs reinforces SOCS2 as a potential therapeutic target for Th2-biased diseases.