92 Moreover, polymorphisms in not only STAT3, but also in IL23R
and JAK2 loci, correlate with Crohn’s disease.93–95 Therefore, appropriate activation of the STAT proteins is clearly required for the development of a healthy immune response. Interestingly, several studies show abnormal expression of SOCS proteins in autoimmune diseases. In particular, SOCS1 mRNA is elevated in patients who present with systemic lupus erythematosus96 and rheumatoid arthritis,97 and single nucleotide polymorphisms in SOCS1 are associated with multiple sclerosis98 and coeliac disease.99 All of these autoimmune pathologies are characterized by increased IL-17 secretion, which would be consistent with the fact that SOCS1 promotes the development of Th17 cells. Compellingly, selleck inhibitor the correlation between SOCS3 expression and the severity of atopy is also apparent in patients. Markedly buy PXD101 elevated SOCS3 expression is observed in skin samples from patients suffering from severe atopic dermatitis (AD) when compared with individuals with normal skin or with the Th1-mediated condition psoriasis.100 Furthermore, specific haplotypes of the SOCS3 gene have been linked with AD in two independent Swedish childhood cohorts
and SOCS3 mRNA is more highly expressed in AD skin.101 The detection of elevated SOCS3 expression in peripheral T cells and in AD skin may be of particular relevance because the SOCS3 gene is located on chromosome 17q25, one of the established AD genetic loci.102 Similarly, SOCS3 expression in T cells positively correlates with the severity of asthma and AD,33 whereas elevated SOCS3 mRNA levels and polymorphisms within second the SOCS3 locus are found in patients with AD.101 Asthmatics also present with polymorphisms within the SOCS1 promoter, consistent with the fact that SOCS3 and SOCS1 regulate Th2 differentiation.103
The correlation between elevated SOCS1 expression and asthma severity in patients suggests that SOCS1 may inhibit IFN-γ-dependent Th1 differentiation, thereby enhancing Th2-mediated pathology.104 Of note, disruption of SOCS2 expression increases murine susceptibility to atopy but whether this is of relevance in patients has yet to be determined.59 Taken together, these different studies confirm the importance of SOCS proteins in the regulation of human pathogenic immune responses. Clearly, both STATs and SOCS are key regulators of lineage commitment and collaborate to tightly regulate CD4+ T-cell polarization. As with STATs, SOCS often exert opposing effects and may cross-regulate one another,59,61,105,106 and although murine null models exemplify this cross-compensation, this may well reflect reality because SOCS proteins are differentially expressed in individual CD4+ lineages.