|Figure 2. FISP expression is dependent upon two different pathways: intact T cell receptor (TCR) signaling via protein kinase C (PKC) and signaling through the IL-4 receptor complex. [Note: figure is adapted from Schaefer, G. et al. (2001) J. Immunol. 166:5859.]|
T helper (Th) lymphocyte subsets can be identified based on their secretion of distinct cytokine profiles and their effector functions.1 Th1-type cytokines include IFN-gamma, TNF-beta, and IL-2, whereas IL-4, IL-5, IL-6, and IL-13 are considered Th2-type cytokines.2,3 Th1 cells are involved in immune responses against intracellular pathogens and also mediate delayed-type hypersensitivity and organ-specific autoimmune diseases. Th2 cells play critical roles in allergic and infectious disease immune responses. The differentiation of Th1 or Th2 cells is influenced by the nature of the antigen responsible for generating the specific immune response, presence of exogenous cytokines, and the select activation of distinct Th1- or Th2-promoting genes.
FISP (IL-4-induced secreted protein) is selectively expressed and secreted by Th2 lymphocytes.4 It was identified using the representational difference analysis method to isolate genes selectively expressed in Th2 cells that may also be important for Th2 cell development. The FISP gene encodes a protein of 220 amino acids with a predicted molecular mass of 25 kDa. The FISP protein is 93% identical with rat mob-5 and 80% identical with human mda-7. It has limited homology with the cytokines IL-10 (33%) and IL-20 (30%) (see Figure 1). Expression of FISP is restricted to Th2 lymphocytes. In addition to Th2-differentiated lymphocytes, an anti-CD3-activated Th2 clone, the D10.G4 cell line, expresses FISP transcripts. By contrast, Th1 lymphocytes and untreated splenocytes do not express FISP. FISP RNA is also not detected in spleen, thymus, liver, brain, heart, lung, testicle, kidney, or embryonic tissues.
Signaling via the IL-4 receptor (IL-4 R) and T cell receptor (TCR) complexes regulates FISP expression. The transcription factor STAT6 is required for IL-4-induced differentiation of Th2 cells.5-7 STAT6-deficient CD4+ cells, derived from STAT6-deficient mice and differentiated under Th2 conditions, lack FISP expression.4 These results suggest that IL-4-mediated signaling is linked to FISP expression in Th2-differentiated cells. Human mda-7 was identified in melanoma cells treated with IFN-beta and mezerein, a non-phorbol ester that activates protein kinase C (PKC).8 Treatment of the Th2 cell line, D10.G4, with mezerein and IL-4 results in elevated levels of FISP, similar to the levels observed with anti-CD3-activation.4 Mezerein or IL-4 treatment alone, however, did not induce FISP expression in D10.G4 cells. Collectively, these data suggest that FISP expression is dependent on signals generated following engagement of both the TCR and IL-4 R (see Figure 2). The exact function that FISP plays in Th2 differentiation, however, remains to be identified. Based on the sequence similarity to mob-5 and mda-7, it appears as if FISP may be a homologue of these two genes.4
|Figure 1. Alignment of the FISP amino acid sequence with rat mob-5, human mda-7, mouse IL-10, and mouse IL-20. Conserved amino acids are highlighted in blue type. The arrow indicates the signal sequence cleavage site. [Note: figure is adapted from Schaefer, G. et al. (2001) J. Immunol. 166:5859.]|