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IL-4 Restores Impaired Contact Hypersensitivity Response in Obese Mice Fed a High-Fat Diet Enriched with Oleic Acid

2007; Elsevier BV; Volume: 128; Issue: 3 Linguagem: Inglês

10.1038/sj.jid.5701122

1523-1747

Kazumoto Katagiri, Shoko Arakawa, Rieko Kurahashi,

Immune Cell Function and Interaction

contact hypersensitivity diet-induced obese high-fat diet normal diet another type of commercially available high-fat diet high-fat and high-calorie diet supplemented with sucrose and safflower oil 2,4,6-trinitrochlorobenzene TO THE EDITOR Data from population studies show that obese people tend to have higher rates of infection and cancer (Choban et al., 1995Choban P.S. Heckler R. Burge J.C. Flancbaum L. Increased incidence of nosocomial infections in obese surgical patients.Am Surg. 1995; 61: 1001-1005PubMed Google Scholar; Engel et al., 2003Engel L.S. Chow W.H. Vaughan T.L. Gammon M.D. Risch H.A. Stanford J.L. et al.Population attributable risks of esophageal and gastric cancers.J Natl Cancer Inst. 2003; 95: 1404-1413Crossref PubMed Scopus (528) Google Scholar). This led us to hypothesize that those who are obese may have impaired immunity mechanisms. Recently, we found that diet-induced obese (DIO) mice had impaired contact hypersensitivity (CHS) responses to 2,4,6-trinitrochlorobenzene (TNCB), but that their Langerhans cell function and delayed-type hypersensitivity response to ovalbumin were not affected (Katagiri et al., 2007Katagiri K. Arakawa S. Kurahashi R. Hatano Y. Impaired contact hypersensitivity in diet-induced obese mice.J Dermatol Sci. 2007; 46: 117-126Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). Thus, the impaired CHS response might be related to obesity; non-obese BALB/c mice that received the same high-fat diet (HFD) did not experience changes in their CHS responses to TNCB (Katagiri et al., 2007Katagiri K. Arakawa S. Kurahashi R. Hatano Y. Impaired contact hypersensitivity in diet-induced obese mice.J Dermatol Sci. 2007; 46: 117-126Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). The HFD has a high fatty-acid content, which might affect the immune response (Yaqoob, 2003Yaqoob P. Fatty acids as gatekeepers of immune cell regulation.Trends Immunol. 2003; 24: 639-645Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). We designed this study to examine the impairment mechanisms that affect CHS response in DIO mice and to determine whether it is the obesity or the HFD that is responsible for the impairment. Female C57BL/6 mice were purchased from Kyudo Co. (Fukuoka, Japan) and were 6-weeks old at the time of experimentation. The mice were treated in accordance with the Oita University Guidelines for the Care and Use of Laboratory Animals. To induce obesity, we fed one group of mice a high-fat, high-calorie diet supplemented with sucrose and safflower oil (oleic acid-rich oil) (S-HFD). The other group of mice was fed a normal diet (ND). During some experiments, a panel of mice was fed a commercially available HFD (O-HFD) (Oriental Yeast Co., Tokyo, Japan), in which the fat consisted of soybean and lard (see details in the figure legends). CHS experiments were performed at least 6 weeks after the mice began their assigned diets. The mice were sensitized with TNCB, oxazolone, or FITC on their shaved abdomens. Seven days later, the ear pinnae were challenged with the same agents. Unsensitized mice fed on the same diets were used as negative controls for each group (see details in the figure legends). In some experiments, DIO and lean mice received an intravenous injection of 100 ng of IL-4 (Peprotech EC, London, UK) in 100 μl of HBSS or HBSS alone immediately before sensitization or challenge with TNCB or FITC. C57BL/6 mice fed on either type of HFD had significantly larger weight gains when compared with mice fed an ND from day 28 until the end of the study (Figure 1a). CHS responses to TNCB and FITC, but not oxazolone, were impaired in DIO mice fed an S-HFD, whereas DIO mice fed an O-HFD did not experience diminished CHS responses to TNCB and FITC (Figure 1b–d). The differing CHS responses to various haptens suggest a defect of the IL-4 signal in S-HFD mice because CHS responses to TNCB and FITC, but not oxazolone, have been shown to depend on IL-4 (Dieli et al., 1999Dieli F. Sireci G. Scire E. Salerno A. Bellavia A. Impaired contact hypersensitivity to trinitrochlorobenzene in interleukin-4-deficient mice.Immunology. 1999; 98: 71-79Crossref PubMed Scopus (45) Google Scholar; Traidl et al., 1999Traidl C. Jugert F. Krieg T. Merk H. Hunzelmann N. Inhibition of allergic contact dermatitis to DNCB but not to oxazolone in interleukin-4-deficient mice.J Invest Dermatol. 1999; 112: 476-482Crossref PubMed Scopus (80) Google Scholar). Therefore, we examined whether exogenous IL-4 restores impaired CHS responses, as it did in IL-4-deficient mice (Dieli et al., 1999Dieli F. Sireci G. Scire E. Salerno A. Bellavia A. Impaired contact hypersensitivity to trinitrochlorobenzene in interleukin-4-deficient mice.Immunology. 1999; 98: 71-79Crossref PubMed Scopus (45) Google Scholar). Administration of IL-4 immediately before either sensitization or challenge restored CHS responses to TNCB and FITC in S-HFD mice, but it did not influence CHS responses in lean mice (Figure 2a–d). We explored the source of IL-4 in the CHS response to TNCB with reference to a previous report (Dieli et al., 1998Dieli F. Taniguchi M. Asherson G.L. Sireci G. Caccamo N. Scire E. et al.Development of hapten-induced IL-4-producing CD4+ T lymphocytes requires early IL-4 production by αβ T lymphocytes carrying invariant Vα14 TCR α chains.Int Immunol. 1998; 10: 413-420Crossref PubMed Scopus (16) Google Scholar), although neither mRNA nor protein of IL-4 was found in harvested regional lymph node cells, the skin 6 and 24 hours after sensitization with TNCB or the culture supernatant by reverse transcription PCR and ELISA of either DIO or lean mice (data not shown).Figure 2IL-4 restored impaired CHS responses to TNCB and FITC in diet-induced obese mice fed an S-HFD. Mice fed the ND or the S-HFD for 6 weeks were sensitized and challenged with TNCB or FITC. Both groups of mice received an intravenous injection of IL-4 (100 ng in 100 μl of HBSS) or HBSS alone immediately (a and c) before sensitization or immediately (b and d) before challenge with TNCB or FITC. Unsensitized mice fed the ND and the S-HFD were used as negative controls (NC). Ear swelling was measured at 24 hours, and the results are represented as the mean±SEM (n=6 mice/group).View Large Image Figure ViewerDownload (PPT) This study reveals that an HFD enriched with oleic acid (S-HFD), and not obesity itself, is essential to impair CHS response to TNCB and FITC, although the effect was limited in the susceptible mice to diet-induced obesity. The significant difference between S-HFD and O-HFD mice was their oleic acid content. We chose oleic acid-rich oil as a fat source since oleic acid is considered less influential in immune response and because it has been used as a control for fatty acids in previous studies (Moison and Beijersbergen van Henegouwen, 2001Moison R. Beijersbergen van Henegouwen G.M. Dietary eicosapentaenoic acid prevents systemic immunosuppression in mice induced by UVB radiation.Radiat Res. 2001; 156: 36-44Crossref PubMed Scopus (31) Google Scholar). Our results suggest that oleic acid's effect on immunity should be re-evaluated in the susceptible mice group. Restoration of the impaired CHS responses by IL-4 indicates the defect of the IL-4 signal in DIO mice fed an S-HFD, although we failed to find the source of IL-4 in our CHS model. Askenase and colleagues reported that IL-4 that is produced by liver NKT cells immediately after sensitization with TNCB leads within a day to the production of antigen-specific IgM by B-1 cells, which is necessary to induce the CHS response by effector T cells (Campos et al., 2003Campos R.A. Szczepanik M. Itakura A. Akahira-Azuma M. Sidobre S. Kronenberg M. et al.Cutaneous immunization rapidly activates liver invariant Vα14 NKT cells stimulating B-1 B cells to initiate T cell recruitment for elicitation of contact sensitivity.J Exp Med. 2003; 198: 1785-1796Crossref PubMed Scopus (149) Google Scholar, Campos et al., 2006Campos R.A. Szczepanik M. Lisbonne M. Itakura A. Leite-de-Moraes M. Askenase P.W. Invariant NKT cells rapidly activated via immunization with diverse contact antigens collaborate in vitro with B-1 cells to initiate contact sensitivity.J Immunol. 2006; 177: 3686-3694Crossref PubMed Scopus (46) Google Scholar; Itakura et al., 2005Itakura A. Szczepanik M. Campos R.A. Paliwal V. Majewska M. Matsuda H. et al.An hour after immunization peritoneal B-1 cells are activated to migrate to lymphoid organs where within 1 day they produce IgM antibodies that initiate elicitation of contact sensitivity.J Immunol. 2005; 175: 7170-7178Crossref PubMed Scopus (61) Google Scholar). Quick administration of IL-4 before either sensitization or challenge might play a role similar to that of NKT cells in CHS induction. Interestingly, a decreased number of liver NKT cells was reported in DIO mice (Li et al., 2005Li Z. Soloski M.J. Diehl A.M. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease.Hepatology. 2005; 42: 880-885Crossref PubMed Scopus (238) Google Scholar). There is a possibility that mast cells in the skin might be a source of early IL-4 production, although we failed to find expression of IL-4 mRNA in the skin 6 and 12 hours after TNCB application. IL-4 injections just before challenge restored CHS responses. This indicates the presence of effector T cells in pre-sensitized DIO mice rather than the impairment of the CHS afferent phase in DIO mice, which was suggested by the failure of adoptive transfer in our previous study (Katagiri et al., 2007Katagiri K. Arakawa S. Kurahashi R. Hatano Y. Impaired contact hypersensitivity in diet-induced obese mice.J Dermatol Sci. 2007; 46: 117-126Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). Interestingly, CHS response to oxazolone in DIO mice seems to be enhanced (Figure 1c), although enhanced nonspecific inflammation, which was seen as an irritant response to hapten, might reinforce the CHS response. An HFD or diet-induced obesity might have a dual effect on CHS response depending on types of hapten or strains of mice. In conclusion, an HFD enriched with oleic acid impairs CHS response to TNCB and FITC in susceptible mice by inducing a lack of IL-4 signal, which might affect immune responses other than CHS. The authors state no conflict of interest. This study was partially supported by a grant from the Kao Research Council for the Study of Healthcare Science.