Chronic Helminth Infections Research Articles

Human cases of simultaneous echinococcosis and tuberculosis - significance and extent in China

During analysis of retrospective community survey data, we identified two patients from Xiji County, south Ningxia Hui Autonomous Region with simultaneous echinococcosis and tuberculosis (TB), representing the first such reports for China. As the echinococcosis chronicity increased, the immune profile in both subjects changed from a Th1 to Th2 response, as shown by a TB skin test, originally positive, becoming negative. Such an elevated Th2 immune profile, with subsequent suppression of the Th1 immune response, is a common feature of chronic helminth infections. Given the difficulties in definitive diagnosis, and the potential increased susceptibility for TB infection in patients with advanced echinococcosis, we suggest that combined TB/echinococcosis surveys be undertaken in this area in the future. This would allow early diagnosis of both TB and echinococcosis cases with better prognosis for effective and sustainable treatment outcomes, ultimately reducing associated morbidity and mortality, and also the overall financial costs to the individual and the public health care system in this under developed part of China.

Adjusting for the Acute Phase Response Is Essential to Interpret Iron Status Indicators among Young Zanzibari Children Prone to Chronic Malaria and Helminth Infections ,

The extent to which the acute phase response (APR) influences iron status indicators in chronic infections is not well documented. We investigated this relationship using reported recent fever and 2 acute phase proteins (APP), C-reactive protein (CRP), and a-1-acid glycoprotein (AGP). In a sample of 690 children matched on age and helminth infection status at baseline, we measured plasma for AGP, CRP, ferritin, transferrin receptor (TfR), and erythropoietin (EPO) and whole blood for hemoglobin (Hb) concentration, zinc protoporphyrin (ZPP), and malaria parasite density, and we obtained maternal reports of recent fever. We then examined the influence of the APR on each iron status indicator using regression analysis with Hb as the outcome variable. Ferritin was inversely related to Hb in the APR-unadjusted model. Adjusting for the APR using reported recent fever alone was not sufficient to reverse the inverse Hb-ferritin relationship. However, using CRP and/or AGP resulted in the expected positive relationship. The best fit model included reported recent fever, AGP and CRP (R2 = 0.241; P < 0.001). The best fit Hb-ZPP, Hb-TfR, and Hb-EPO models included reported recent fever and AGP but not CRP (R2 = 0.253, 0.310, and 0.292, respectively; P < 0.001). ZPP, TfR, and EPO were minimally influenced by the APR, whereas ferritin was immensely affected. Reported recent fever alone cannot be used as a marker for the APR. Either AGP or CRP is useful for adjusting if only 1 APP can be measured. However, AGP best predicted the APR in this population.

Persistent Eosinophilia and Strongyloides Infection in Montagnard Refugees after Presumptive Albendazole Therapy

Chronic helminth infections are common in refugee populations and may persist years after immigration. Asymptomatic Strongyloides stercoralis infection raises particular concern because of its potential for complications in immunosuppressed patients. We examined 172 Montagnard refugees resettled to Wake County, North Carolina from 2002 through 2003. Refugees were pretreated with albendazole for five days and screened for health conditions after arrival. Eosinophilia was present in 41 of 171 refugees at the first blood draw. Only 1 of 172 had a stool helminth (Fasciola) identified by microscopy. On repeat testing, 13 people had persistent eosinophilia. Results of serologic analysis for Strongyloides were available in 24 persons. Eosinophil counts decreased significantly after treatment with ivermectin in nine refugees (P = 0.039). Persistent eosinophilia, likely caused by Strongyloides infection, was common in this cohort of Montagnard refugees. Clinicians should understand the limitations of stool microscopy in diagnosis of strongyloidiasis, the limited effectiveness of albendazole in treating strongyloidiasis, and the importance of following-up refugees with persistent eosinophilia.

Schistosoma mansoni coinfection could have a protective effect against mixed cryoglobulinaemia in hepatitis C patients

The association between mixed cryogloblinaemia and chronic hepatitis C virus (HCV) infection has been established. However, the factors underlying its great geographical heterogeneity of prevalence have not yet been identified. Concomitant HCV and Schistosoma mansoni infections are common in Egypt. Chronic helminthic infections have been found to decrease the incidence and manifestations of immune-related diseases. To date, no study has focused on the influence of S. mansoni coinfection on the risk of cryoglobulinaemia in hepatitis C patients. A cohort of 119 consecutively recruited chronic hepatitis C-infected patients was studied. Patients' sera were assessed for S. mansoni antibodies and cryoglobulins (CGs) were determined and characterized. Cryoglobulins were detected in 18 of 119 patients (15.1%) included in this study. They were detected in 12 of 45 hepatitis C (26.7%) and six of 74 coinfected patients (8.1%), which was statistically significant, P=0.01. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were also found to be significantly lower in the CG-positive group compared with the CG-negative group, P=<0.01. CGs were detected in seven of 21 (33.3%) and in 11 of 98 (11.2%) hepatitis C female and male patients, respectively, indicating a significantly positive association with the female gender, P=0.02. A logistic regression adjusted for gender, AST and ALT showed that hepatitis C patients without schistosomal coinfection are more likely to have cryoglobulinaemia, odds ratio=4.12, 95% confidence interval=1.42-11.95. There is an apparent protective effect of S. mansoni coinfection against mixed cryoglobulinaemia in chronic hepatitis C patients.

Regulation of Helminth-Induced Th2 Responses by Thymic Stromal Lymphopoietin

Thymic stromal lymphopoietin was recently identified as a master switch for the development of allergen-driven Th2 responses. However, the role of thymic stromal lymphopoietin (TSLP) in the development of helminth-induced Th2 responses is unclear. Here, using TSLPR(-/-) mice, we show that while TSLPR signaling participates in the development of Schistosoma mansoni egg-induced CD4(+) Th2 responses, it plays only a transient role in the development of Th2-dependent pathology in the lung, liver, and intestine. Studies conducted in a pulmonary granuloma model showed that while a reduction in IL-4/IL-13-dependent granulomatous inflammation and tissue eosinophilia was observed in TSLPR(-/-) mice undergoing a primary response, lesion formation was not affected during a secondary granulomatous response, even though IL-5 and IL-13 were modestly reduced in the knockout mice. To evaluate the importance of TSLPR signaling in the development of a chronic Th2-dependent response, TSLPR(-/-) mice were also infected with S. mansoni cercariae. Here, the only significant difference noted in TSLPR(-/-) mice was a modest decrease in liver fibrosis in acutely infected animals. The transient decrease in fibrosis was associated with increased production of the antifibrotic cytokine IFN-gamma and decreased production of the profibrotic cytokine IL-13. Although the altered cytokine response persisted in chronically infected TSLPR(-/-) mice, it failed to reduce granuloma formation or fibrosis, confirming that TSLPR signaling plays a limited role in the development of chronic Th2-dependent pathology. Collectively, these findings suggest that while TSLPR signaling serves a key role in allergen-driven Th2 responses, it exerts minor regulatory activity during this chronic helminth infection.

Suppression of airway inflammation by a natural acute infection of the intestinal epithelium

Although chronic intestinal helminth infections may suppress allergen-induced airway pathology by inducing a combination of modified T-helper (Th) 2 and immunosuppressive cytokines, a similar capacity of natural acute intestinal infections has remained untested, despite their global prevalence. Here, we show that allergic airway phenotypes including eosinophilia, eotaxin mRNA, and Th2 cytokines are significantly suppressed in animals that were infected by and that have cleared the intestinal parasite Eimeria vermiformis. Unlike in helminth-infected animals, regulation requires temporal coincidence of infection with sensitization; depends on interferon-γ; and is not associated with an enhanced antigen-specific immunoglobulin G1 response. Moreover, regulation was effective following allergen sensitization in different anatomical sites, and in young and adult mice. These data highlight a transient anatomical dissemination of “functional immunologic dominance” following infection of the gut mucosa. They strongly support the hypothesis that airway allergies are naturally suppressed by both acute and chronic mucosal pathogens, but by different mechanisms.

Regulatory T Cells: A Role in the Control of Helminth-Driven Intestinal Pathology and Worm Survival

The chronic nature of intestinal nematode infections suggests that these parasites have evolved sophisticated immunomodulatory strategies. The induction of regulatory responses during chronic helminth infections could be advantageous to the host by minimizing damage incurred by these organisms. Regulation of the host immune response to infection could however be exploited by parasites as a survival strategy. We have explored both these aspects using the murine model of whipworm infection, Trichuris muris. Of the three laboratory isolates of T. muris in use, two (the E (Edinburgh) and J (Japan, subcultured from E)) are readily expelled by C57BL/6 mice, whereas the third, the S isolate (Sobreda, isolated from wild mice in Portugal) survives for much longer. The existence of the T. muris isolates thus presents a powerful tool to explore the mechanisms underlying chronic infection in a single strain of mouse. In this study, we show that S isolate-infected mice have increased numbers of Foxp3(+) T cells in the gut compared with mice infected with the E isolate. Treatment of mice infected with the S isolate with either anti-CD25 or anti-glucocorticoid-induced TNFR exacerbated intestinal pathology, and, in addition, mice treated with anti-glucocorticoid-induced TNFR were able to expel worms more rapidly, implying the release of local effector mechanisms from a regulatory influence. Thus, our data show for the first time that T regulatory cells protect the host from worm-driven intestinal pathology. In addition, our data reveal a subversion of this damage-limiting response by the S isolate to facilitate its own survival.

Proteomics Analysis of the Excretory/Secretory Component of the Blood-feeding Stage of the Hookworm, Ancylostoma caninum

Hookworms are blood-feeding intestinal parasites of mammalian hosts and are one of the major human ailments affecting approximately 600 million people worldwide. These parasites form an intimate association with the host and are able to avoid vigorous immune responses in many ways including skewing of the response phenotype to promote parasite survival and longevity. The primary interface between the parasite and the host is the excretory/secretory component, a complex mixture of proteins, carbohydrates, and lipids secreted from the surface or oral openings of the parasite. The composition of this complex mixture is for the most part unknown but is likely to contain proteins important for the parasitic lifestyle and hence suitable as drug or vaccine targets. Using a strategy combining the traditional technology of one-dimensional SDS-PAGE and the newer fractionation technology of OFFGEL electrophoresis we identified 105 proteins from the excretory/secretory products of the blood-feeding stage of the dog hookworm, Ancylostoma caninum. Highly represented among the identified proteins were lectins, including three C-type lectins and three beta-galactoside-specific S-type galectins, as well as a number of proteases belonging to the three major classes found in nematodes, aspartic, cysteine, and metalloproteases. Interestingly 28% of the identified proteins were homologous to activation-associated secreted proteins, a family of cysteine-rich secreted proteins belonging to the sterol carrier protein/Tpx-1/Ag5/PR-1/Sc-7 (TAPS) superfamily. Thirty-four of these proteins were identified suggesting an important role in host-parasite interactions. Other protein families identified included hyaluronidases, lysozyme-like proteins, and transthyretin-like proteins. This work identified a suite of proteins important for the parasitic lifestyle and provides new insight into the biology of hookworm infection.

Filarial infection induces protection against P. berghei liver stages in mice

Chronic helminth infections such as filariasis in human hosts can be life long, since parasites are equipped with a repertoire of immune evasion strategies. In many areas where helminths are prevalent, other infections such as malaria are co-endemic. It is still an ongoing debate, how one parasite alters immune responses against another. To dissect the relationships between two different parasites residing in the same host, we established a murine model of co-infection with the filarial nematode Litomosoides sigmodontis and the malaria parasite Plasmodium berghei (ANKA strain). We found that filarial infection of BALB/c mice leads to protection against a subsequent P. berghei sporozoite infection in one-third of co-infected mice, which did not develop blood-stage malaria. This finding did not correlate with adult worm loads, however it did correlate with the presence of microfilariae in blood. Interestingly, protection was abrogated in IL-10-deficient mice. Thus, murine filariasis, in particular when it is a patent infection, is able to modify the immunological balance to induce protection against an otherwise deadly Plasmodium infection and is therefore able to influence the course of malaria in favour of the host.

Orthologs of macrophage migration inhibitory factor from parasitic nematodes

Chronic helminth infections are associated with modulation of host cellular immune responses, presumably to prolong parasite survival within the mammalian host. This phenomenon is attributed, at least in part, to the elaboration of parasite molecules, including orthologs of host cytokines and receptors, at the host-parasite interface. This review describes recent progress in the characterization of macrophage migration inhibitory factor (MIF) orthologs from parasitic nematodes. The roles of these molecules in parasite developmental biology and pathogenesis are discussed. Further knowledge of the species-specific activities and three-dimensional structures of human and parasitic nematode MIF molecules should make them ideal targets for drug- and/or vaccine-based strategies aimed at nematode disease control.

Eosinophilia during intestinal infection

Eosinophilia is a common finding in tropical developing countries, and is mainly caused by chronic helminth infections, predominantly of the gut. Although only a minority of infections is symptomatic, development during childhood can be impaired, and in some patients serious complications and sequelae may occur. Eosinophilia in helminth infection is typically associated with a strong Th2 immune response, and eosinophils can effectively kill or damage larvae and adult worms in vitro. However, in vivo, eosinophils are only partly effective in the control of helminth infection, and recent research has shown that eosinophils are involved in a range of immunomodulatory effects, such as increased production of the down-modulatory cytokines interleukin 10 and tumour growth factor beta, as well as stimulation of regulatory T cells and alternatively activated macrophages. Increasing evidence suggests that immunomodulation favours parasite survival and reduces immune pathology. On the other hand, immunomodulation induced by helminth infections may contribute to protection from allergic and autoimmune responses, as proposed by the 'hygiene hypothesis' to explain the increase in allergic diseases in the industrialised world. The predictive value of eosinophilia for the presence of helminth infections is limited and depends on the epidemiological background and the extent of the eosinophilia. It increases considerably in populations with a high prevalence of parasitic infections, as in developing tropical countries or in travellers to those areas.

Concurrent gastro-intestinal nematode infection does not alter the development of experimental cerebral malaria

Concurrent helminth infections have been suggested to be associated with protection against cerebral malaria in humans, a condition characterised by systemic inflammation. Here we show that a concurrent chronic gastro-intestinal nematode infection does not alter the course of murine cerebral malaria. Mice infected with Heligmosomoides polygyrus, and co-infected with Plasmodium berghei ANKA 14 days later, developed malaria parasitemia, weight loss and anemia, at the same rate as mice without nematode infection. Both groups developed cerebral malaria around the same time point. The data suggest that a chronic helminth infection does not affect the development of cerebral malaria in a murine model.

Helminth–HIV Coinfection: Should We Deworm?

The prevalence of helminthic infections in most of the developing countries is overwhelming, and almost a quarter of the world's population is infected by them. Likewise, with the spread of the AIDS epidemic, dual helminthic and HIV-1 coinfections are extremely common, particularly in Africa [1]. Several years ago we suggested that helminth infections play a major role in the pathogenesis of HIV-1 infection in Africa and other developing countries, due to their profound effects on the host immune system, which would make those infected with helminths more susceptible to HIV-1 infection and more vulnerable to the disease's effects [2]. As summarized in three more recent reviews, we and others have demonstrated that chronic immune activation with a dominant T helper cell 2 profile, and anergy, are indeed the hallmarks of chronic helminth infection [3]–[5]. These immune changes are characterized by several modulations in the normal immune response, particularly those of the cellular immune response, which together could account for possible profound effects of the chronic helminthic infection on the host's ability to handle HIV as well as other infections. Importantly, most of these modulations are reverted almost completely to normal following treatment of the helminthic infections.

IL-13Rα2 and IL-10 coordinately suppress airway inflammation, airway-hyperreactivity, and fibrosis in mice

Development of persistent Th2 responses in asthma and chronic helminth infections are a major health concern. IL-10 has been identified as a critical regulator of Th2 immunity, but mechanisms for controlling Th2 effector function remain unclear. IL-10 also has paradoxical effects on Th2-associated pathology, with IL-10 deficiency resulting in increased Th2-driven inflammation but also reduced airway hyperreactivity (AHR), mucus hypersecretion, and fibrosis. We demonstrate that increased IL-13 receptor alpha 2 (IL-13Ralpha2) expression is responsible for the reduced AHR, mucus production, and fibrosis in BALB/c IL-10(-/-) mice. Using models of allergic asthma and chronic helminth infection, we demonstrate that IL-10 and IL-13Ralpha2 coordinately suppress Th2-mediated inflammation and pathology, respectively. Although IL-10 was identified as the dominant antiinflammatory mediator, studies with double IL-10/IL-13Ralpha2-deficient mice illustrate an indispensable role for IL-13Ralpha2 in the suppression of AHR, mucus production, and fibrosis. Thus, IL-10 and IL-13Ralpha2 are both required to control chronic Th2-driven pathological responses.

Protective effect of Schistosoma mansoni infection on allergic airway inflammation depends on the intensity and chronicity of infection

Population studies have suggested that chronic and intense helminth infections, in contrast to acute and mild helminth infections, might suppress allergic airway inflammation. We sought to address the question of how the chronicity and intensity of helminth infections affect allergic airway inflammation in a well-defined experimental model. C57/Bl6 mice were infected with Schistosoma mansoni, followed by sensitization and challenge with ovalbumin (OVA), and different stages and intensities of infection were studied. To this end, mice were analyzed at 8, 12, or 16 weeks, representing the acute, intermediate, or chronic phases of infection, respectively. Lung lavage eosinophilia, peribronchial inflammation, and OVA-induced airway hyperresponsiveness were increased during acute infection but significantly decreased when infection progressed into chronicity. Decreases in lung lavage eosinophilia were parasite density-dependent. Similar levels of OVA-specific IgE were found during all phases of infection, whereas both OVA-specific and parasite-specific T(H)2 cytokine levels were significantly reduced during chronic infection. Inhibition of airway inflammation could be transferred to OVA-sensitized recipient mice by B cells and CD4(+) T cells from spleens of chronically, but not acutely, infected mice. This suppression was IL-10-dependent. During chronic, but not acute, helminth infections, suppressive mechanisms are induced that regulate immune reactions to inhaled allergens. These data confirm human epidemiologic observations in a well-controlled animal model. Characterization of chronic helminth infection-induced regulatory mechanisms will help in the development of future therapeutics to treat or prevent allergic disease.

Expansion and activation of CD4(+)CD25(+) regulatory T cells in Heligmosomoides polygyrus infection.

Regulatory T cell responses to infectious organisms influence not only immunity and immunopathology, but also responses to bystander antigens. Mice infected with the gastrointestinal nematode parasite Heligmosomoides polygyrus show an early Th2-dominated immune response (days 7–14), but by day 28 a strongly regulatory profile is evident with antigen-specific IL-10 release and elevated frequency of CD4+ T cells bearing surface TGF-β. CD4+CD25+ T cells from infected mice show enhanced capacity to block in vitro effector T cell proliferation. CD4+CD25+ cell numbers expand dramatically during infection, with parallel growth of both CD25+Foxp3+ and CD25+Foxp3– subsets. CTLA-4 and glucocorticoid-induced tolerance-associated receptor, also associated with regulatory T cell function, become more prominent, due to both expanded CD25+ cell numbers and increased expression among the CD25– population. Both intensity and frequency of CD103 expression by CD4+ T cells rise significantly, with greatest expansion among CD25+Foxp3+ cells. While TGF-β expression is observed among both CD25+Foxp3+ and CD25+Foxp3– subsets, it is the latter population which shows higher TGF-β staining following infection. These data demonstrate in a chronic helminth infection that Foxp3+ regulatory T cells are stimulated, increasing CD103 expression in particular, but that significant changes occur to other populations including expansion of CD25+TGF-β+Foxp3– cells, and induction of CTLA-4 on CD25– non-regulatory lymphocytes.

Chronic helminth infections may negatively influence immunity against tuberculosis and other diseases of public health importance

Tuberculosis (TB) has once again become a major public health threat owing to the combined effects of deteriorating socioeconomic situations and the emergence of the HIV/AIDS pandemic. The only vaccine available against TB, although effective in reducing the burden of childhood TB, shows enormous variability in its efficacy against pulmonary TB, which is the most common form of the disease in adults. Most areas of high TB incidence and poor TB vaccine efficacy have a high prevalence of intestinal helminth infections. Such infections have been shown to cause a range of immunomodulation characterized by enhanced T helper 2-type cytokine profile, high immunoglobulin E levels and upregulated regulatory T-cell activity, as well as chronic immune activation. An altered background immune profile could have adverse effects on the outcome of subsequent infections and vaccinations. In support of this hypothesis, studies conducted in animals and humans living in worm-endemic areas have shown that helminths impair resistance against a number of infections of major public health importance, including TB, malaria and HIV/AIDS. Understanding such interactions could assist in the design of vaccines against these diseases.

Chronic helminth infections induce immunomodulation: Consequences and mechanisms

Worldwide, more than a billion people are infected with helminths. These worm infections generally do not lead to mortality, however, they are chronic in nature and can lead to considerable morbidity. Immunologically these infections are interesting; chronic helminth infections are characterized by skewing towards a T helper 2 type response as well as regulatory responses. The regulatory network is associated with chronic helminth infections and is thought to prevent strong immune responses against parasitic worms, allowing their long-term survival and restricting pathology. This regulatory network is thought to also temper responses to non-helminth antigens, like allergens or self-antigens, possibly leading to lower prevalence of allergies and autoimmune diseases in subjects that are chronically infected with helminths. This raises the interesting idea that helminths may bear molecules that have potential therapeutic action against allergies and possibly other inflammatory diseases. However, on the other side of the coin, this would predict that helminth infected subjects might not respond strongly to third party antigens like vaccines. This is an important issue, since most vaccines that are being developed against diseases such as HIV, tuberculosis or malaria will be introduced in areas where helminth infections are highly prevalent. Moreover, these vaccines are proving difficult to develop and are often weak, thus any confounder that would affect their efficacy needs to be taken into consideration. Helminth derived molecules have been identified that induce T helper 2 and regulatory responses via modulation of dendritic cells and some appear to do so via Toll like receptor (TLR) signaling. New insights into these pathways could be useful to antagonize suppression and hence boost vaccine efficacy or to optimize suppression induced by helminth derived molecules and control inflammatory diseases.

Higher serum concentrations of DHEAS predict improved nutritional status in helminth-infected children, adolescents, and young adults in Leyte, the Philippines.

Pubertal development and associated downmodulation of proinflammatory cytokines may predict improved nutritional status, independent of chronic parasite infections, in developing countries. We enrolled 731 individuals, aged 7-30 y, from Leyte, the Philippines, where helminth infections and nutritional morbidity are highly prevalent. The following data were collected: venous blood hemoglobin and serum concentrations of ferritin, dehydroepiandrosterone sulfate (DHEAS), C-reactive protein and proinflammatory cytokines (IL-1, IL-6, TNF-alpha, and soluble TNF receptor I); anthropometric measurements to calculate upper arm muscle area Z-score and sum of triceps and subscapular skinfolds Z-score; stool samples to determine Schistosoma japonicum and geohelminth egg counts; and responses to questionnaires assessing socio-economic status. In cross-sectional multilevel linear and logistic regression analyses adjusted for confounders, relations were assessed between 1) DHEAS and nutritional status, 2) DHEAS and proinflammatory cytokines, and 3) nutritional status and proinflammatory cytokines. Independent of age, socio-economic status, and helminth infections, increased levels of DHEAS were associated with improved nutritional status and decreased prevalence of non-iron deficiency anemia in both males and females. DHEAS showed dose-dependent inverse associations with C-reactive protein (P=0.08) and the production of IL-6 (P<0.0001). These inflammatory markers, in turn, were consistently associated with undernutrition and anemia. The results suggest that the puberty-associated rise in DHEAS downmodulates proinflammatory immune responses and thereby reduces undernutrition and anemia in a population experiencing a high burden of chronic helminth infections. This novel regulatory mechanism of inflammation-related nutritional morbidity emphasizes the importance of treating prepubescent children for helminth infections.

Chronic helminth infections modulate allergen‐specific immune responses: Protection against development of allergic disorders?

Inflammatory diseases are on the rise in westernized countries, but also in urbanized areas of developing countries. A number of studies have now demonstrated a negative association between helminth infections and inflammatory diseases, such as allergy, suggesting a potential role for helminth‐induced immune responses. However, this is not the case for all studies. In this review both supporting and opposing literature on the role of helminth infections, particularly in allergy, are discussed. Furthermore, the concept is put forward that chronic helminth infections, but not acute infections, may be associated with the expression of regulatory networks necessary for downmodulating allergic immune responses to harmless antigens. Lastly, different components of helminth‐induced regulatory networks are detailed, such as the role of regulatory T and B cells, modulation of dendritic cells, the presence of suppressory alternatively activated macrophages, and their individual contributions to protection against allergic diseases. Advantage should be taken from this knowledge to identify and select individual helminth‐derived molecules that may harbor therapeutic potential against inflammatory diseases.