Interactions IL-4 - IFN

C protein-induced myositis (CIM) is a mouse model of polymyositis, in which activated antigen-specific CD8+ T cells injure the muscles. Autoimmune animal models examined in the past for the effects of type-1 and type-2 cytokines, interferon (IFN) -γ and interleukin (IL) -4, are all mediated by pathogenic CD4+ T cells. In those models, the disruption of IFNγ leads to upregulation of IL-17A, exacerbating the diseases with neutrophil infiltration into the inflammatory sites. IFNγ but not IL-4 has a suppressive role in the development of CIM. Unlike CD4 T cell-mediated autoimmune disease models, IFNγ prevents factors other than IL-17A from exacerbating myositis and neutrophil infiltration. (1)

By measuring the culture supernatant cytokines and the intracellular cytokine-bearing T cell frequencies, we found that the expanded T cells were comprised predominantly of IFN-γ-producing Th1 and IL-4-producing Th2 cells. (1)

Imbalance

cytokine imbalance is postulated in various autoimmune disorders. Th1 cytokines play a role in cell-mediated immunity, but are detrimental in organ-specific responses; Th2 cytokines induce antibody production and mediate allergic responses. Furthermore, Th1 and Th2 cytokine responses are antagonistic and downregulate each other.

Interferon-gamma (IFN) is a T cell-derived Th1 cytokine and a strong inducer of major histocompatibility complex class I expression in IIM inflammatory muscle tissue. The IFN gene on chromosome 12q14 comprises four exons . A variable dinucleotide repeat, (CA)n, has been shown in intron 1, acting as a non-specific tissue enhancer element. (CA) repeat variations are associated with various autoimmune diseases. In contrast, interleukin-4 (IL-4) is a Th2 cytokine produced by activated T cells and functions as a B-cell growth factor. The IL-4 gene is on chromosome 5q31.1, comprising 4 exons (fig 1). IL-4 single nucleotide polymorphisms (SNPs) have been associated with patients having severe asthma and multiple sclerosis.Variable expression of IL-4 and IFN has been shown in IIM muscle biopsy specimens.(2)

Upregulation of cytokines il-4 was strongest at sites of cellular infiltration typical for the respective myositis subtype. Expression of cytokines by the muscle fiber may enable the muscle fiber to induce and mediate the process of autoimmunization and antigen-expression by itself without primary presence of inflammatory cells. Cytokine-expressing muscle fibers may enhance the cytolytic potential of cytotoxic cells and the muscle fiber may serve as source and target (3)

What’s next

IFNγ but not IL-4 has a suppressive role in the development of CIM. Unlike CD4 T cell-mediated autoimmune disease models, IFNγ prevents factors other than IL-17A from exacerbating myositis and neutrophil infiltration (1).

Type I IFN and type I IFN-induced genes were found to play a role in the pathogenesis of connective tissue diseases such as polymyositis and systemic sclerosis (SSc). Patients treated with IFN alpha or IFN beta often produce antinuclear auto-antibodies, which may lead to development of autoimmune diseases so maybe that targeting the therapeutic options in this way may improve the treatment.

 

Footnotes

1. Yoko Y. Interferon-gamma but not interleukin-4 restrains experimental polymyositis.DOI: 10.1002/art.39592. 2016, American College of Rheumatology. http://onlinelibrary.wiley.com/doi/10.1002/art.39592/abstract

2. Hector C.Interferon-gamma and interleukin-4 gene polymorphisms in Caucasian idiopathic inflammatory myopathy patients in UK. Ann Rheum Dis 2007;970–973. doi: 10.1136/ard.2006.068858. http://ard.bmj.com/content/66/7/970.full.pdf

3. Yvkalano F. Positive association between STAT4 polymorphisms and polymyositis/dermatomyositis in a Japanese population Ann Rheum Dis 2012;71:10 1646-1650 . http://ard.bmj.com/content/66/7/970.short