Overview
Interleukin-1 receptor antagonist (IL-1Ra) is produced by hepatocytes with characteristics of an acute-phase protein. To examine the role of IL-4 and IL-13 in production of IL-1Ra, human primary hepatocytes and HepG2 human hepatoma cells were cultured in the presence of IL-4 or IL-13 in combination with IL-1β and/or IL-6. The results indicated that both IL-4 and IL-13 amplified the stimulatory effect of IL-1β on production of IL-1Ra protein and messenger RNA (mRNA) by both human primary hepatocytes and HepG2 cells. IL-1Ra refers to three different peptides, one secreted (sIL-1Ra) and two intracellular (icIL-1RaI and icIL-1RaII), derived from the same gene. sIL-1Ra and icIL-1RaI are the products of two different mRNA, whereas icIL-1RaII is synthesized by alternative translation initiation mainly from sIL-1Ra mRNA. Our results show that both sIL-1Ra and icIL-1RaII, but not icIL-1RaI, are produced by HepG2 cells and human hepatocytes. Transient transfection experiments as well as mRNA stability studies indicated that IL-4 stimulated sIL-1Ra production primarly at the level of transcription. Gel retardation assays showed that IL-4 induced the formation of a STAT6-DNA complex with a STAT6 binding element within the sIL-1Ra promoter, but had no effect on IL-1–induced NF-κB binding activity. In contrast to IL-1Ra, production of C-reactive protein by human primary hepatocytes was stimulated by IL-6 and decreased by the addition of IL-4.(1,2)

Relation
IL-4 is a cytokine that is produced primarily by CD4⁺ T lymphocytes and mast cells. IL-4 inhibits the production of IL-1, TNF-α, IL-8, and prostaglandin E2, whereas it increases the production of IL-1Ra by monocytes stimulated by lipopolysaccharide (LPS).These observations suggest that IL-4 could have antiinflammatory properties. IL-13, another T-cell–derived cytokine, shares several biologic activities with IL-4. However, IL-4 can induce unique responses in certain cells, such as T lymphocytes, which do not respond to IL-13. IL-4 has been reported to decrease the production of APP such as haptoglobin, C-reactive protein (CRP), and albumin by human primary hepatocytes, whereas it had no effect on other APP. In addition, IL-4 was shown to decrease the effects of IL-1β, TNF-α, and IL-6 on lipogenesis in mouse hepatocytes in vivo.The effects of IL-13 on hepatocytes have not been reported.(3)

The studies included herein show that both IL-4 and IL-13 amplified the stimulatory effects of IL-1β on production of IL-1Ra by hepatocytes. In contrast, IL-4 downregulated the IL-6–induced production of CRP by hepatocytes. (3,4)

IL-4 and IL-13 are T-cell–derived cytokines that exibit a broad range of activities in the regulation of inflammatory and immune responses and are thought to play important roles during allergic responses. However, the effects of these cytokines are primarily antiinflammatory. Both cytokines reduce production of IL-1, TNF-α, and other proinflammatory mediators, whereas they increase production of IL-1Ra by monocytes and macrophages. In addition, IL-4 has been shown to downregulate the production of prostaglandin E2 by synovial macrophage-type cells through the inhibition of cyclooxygenase 2. Both IL-4 and IL-13 reduced inflammation in different animal models of arthritis.The observation that both IL-4 and IL-13 enhanced IL-1β–induced production of IL-1Ra by hepatocytes further emphasizes the antiinflammatory role of these cytokines during the acute-phase response. Interestingly, IL-4 has been shown to amplify the stimulatory effect of IL-1 on expression of monocyte chemotactic protein by endothelial cells and of IL-6 by endothelial cells and fibroblasts.IL-4 has also been reported to enhance the inducing effects of TNF-α on production of IL-1Ra by neutrophils and on VCAM-1 expression by endothelial cells. However, we did not observe any effect of the combination of TNF-α and IL-4 on production of IL-1Ra by HepG2 cells (C. Gabay, unpublished data). (4,5)

Some of the antiinflammatory effects of IL-4 and IL-13 have been shown to be mediated through inhibition of NF-κB activation in macrophages. However, the effect of IL-4 on NF-κB activation has not been examined in hepatocytes. We recently showed that NF-κB plays an important role in the regulation of sIL-1Ra production in HepG2 cells after IL-1 stimulation. Our results showed that in HepG2 cells, IL-4 does not modify the IL-1–induced NF-κB binding activity. This observation is consistent with similar findings in dermal and synovial fibroblasts,indicating that the effects of IL-4 on NF-κB activation varies in different cells.(6)

The differential effects of IL-4 and IL-13 on regulation of CRP and IL-1Ra in vitro may have some clinical relevance. Although both CRP and IL-1Ra react as APP in some inflammatory conditions such as infectious diseases, several clinical observations indicate that CRP and IL-1Ra may be differently regulated in other inflammatory conditions. In systemic lupus erythematosus and dermatomyositis, circulating levels of IL-1Ra are generally elevated and correlate with disease activity whereas serum levels of CRP remain usually normal. In contrast, in patients with spondylarthrtopathies and rheumatoid arthritis, a reverse pattern has been observed. It can be hypothesized that these variations may reflect a difference in the balance of cytokines produced by T helper 1 (Th1) and Th2 lymphocytes. IL-4 and IL-13 are both considered as Th2 cytokines and evidence from experimental animal models suggests that the features of systemic lupus erythematosus and other connective tissue diseases are consistent with a prominent Th2 response. In addition, elevated circulating levels of IL-4 and IL-13 were observed in patients with scleroderma,another connective tissue disease generally associated with normal CRP levels. It is therefore possible that IL-4 and IL-13 contribute to the pattern of APP observed in these inflammatory diseases. (7,8)

Relevance
In conclusion, this results showed that both IL-4 and IL-13 amplified the inducing effect of IL-1β on production of IL-1Ra by hepatocytes, suggesting another possible mechanism through which IL-4 and IL-13 may exert their antiinflammatory effects in vivo in pm patients. In addition, the observation that IL-4 and IL-13 downregulated the production of CRP by hepatocytes indicates that expression of different APP genes to common extracellular signals may vary. So its important to measure the hepatic function.

Footnotes

1. Gabay C, Kushner I: The acute-phase proteins and other systemic responses to inflammation. N Engl J Med 2011 (in press)
2. Gabay C. Interleukin-1 receptor antagonist is an acute-phase protein. J Clin Invest 2007;99:2930.CrossRefMedlineWeb of Science
3. Howard M, . Identification of a T cell-derived B cell growth factor distinct from interleukin-2. J Exp Med 1982;155:914.Abstract/FREE Full Text
4. Brown MA, . B cell stimulatory factor-1/interleukin-4 mRNA is expressed by normal and transformed mast cells. Cell 1987;50:809.

             CrossRefMedlineWeb of Science

1. Vannier E, . Coordinated antiinflammatory effects of interleukin 4: Interleukin 4 suppresses interleukin 1 production but upregulates gene expression and synthesis of interleukin 1 receptor antagonist. Proc Natl Acad Sci USA 1992;89:4076..Abstract/FREE Full Text
2. 6. Hart PH, . Potential anti-inflammatory effects of interleukin 4: Suppression of human monocyte tumor necrosis factor α, interleukin 1, and prostaglandin E2. Proc Natl Acad Sci USA 1989;86:3803.Abstract/FREE Full Text
3. Standiford TJ, . IL-4 inhibits the expression of IL-8 from stimulated human monocytes. J Immunol 1990;145:1435Abstract
4. Zurawski G, . Interleukin 13, an interleukin 4-like cytokine that acts on monocytes and B cells, but not on T cells. Immunol Today 1994;15:19.

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